Journal of Glycobiology
Open Access

Glycobiology-Targeted Therapies in Hematologic Oncology: Ushering in a New Era of Cancer Diagnostics and Therapeutics

Ashraf Abdullah Saad^{* *}Correspondence: Ashraf Abdullah Saad, Department of Pediatric Hematologic Oncology and BMT, Sultan Qaboos University Hospital, Muscat, Oman, Email:

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Introduction

Anti-tumor immunity is the basis for durable disease-free treatment-free survival in cancer patients [1]. Historically, the idea of harnessing the immune system to fight cancer had been actively investigated since the early 1900s when William Cooley attempted to cure advanced sarcoma with heat-inactivated bacterial toxins [2,3]. After a century of intense efforts, immunotherapy is currently established as the fifth pillar of cancer therapeutics, joining surgery, cytotoxic chemotherapy, molecularly targeted therapy, and radiation therapy [4].

Currently, the main cancer immunotherapy constructs include Antibody–Drug Conjugates (ADCs), bispecific Antibodies (bsAbs) such as Bispecific T cell engagers (BiTEs), Dual Affinity Retargeting antibodies (DARTs), and Bispecific Killer Cell Engagers (BiKEs) [5], and Chimeric Antigen Receptor (CAR)-T cells. Cancer immunotherapy, named ‘breakthrough of the year 2013’ [6,7] and ‘the cancer advance of the year 2016’ [8], has led to unprecedented and durable response rates in several cancers [9,10]. Nonetheless, the majority of patients do not benefit from cancer immunotherapies and some responders relapse after a period of response [11]. Sharma et al., [12] classified immune resistance into three main categories: primary (a clinical scenario where a cancer does not respond to an immunotherapy strategy), adaptive (appearance of resistance mechanisms as a Darwinian mechanism of adaptation), and acquired/secondary (a clinical scenario in which a cancer initially responded to immunotherapy but after a period of time it relapsed and progressed).

Remarkably, tumor cell-extrinsic mechanisms that lead to primary and/or adaptive resistance involve components within the Tumor MicroEnvironment (TME) (other than tumor cells) which contribute to inhibition of anti-tumor immune responses. The immunosuppressive TME had long been incriminated in chemoresistance as well as now considered the root cause of resistance to the majority of cancer immunotherapies leading to their failure [13,14,15,16]. Notably, T-cell exhaustion (including CAR T-cell exhaustion) [17,18], is a cardinal feature of the TME that eventually result in tumor escape [19,20,21]. The hallmark of exhausted T-cells is their expression of multiple co-inhibitory receptors that operate the immune escape of target tumor cells [22,23]. These co-inhibitory receptors (also referred to as inhibitory immune checkpoints or T-cell exhaustion markers) are the intrinsic brakes of the immune system that protect against autoimmunity under homeostatic conditions. Mechanistically, these T-cell exhaustion markers (Table-1) limit the strength and duration of immune responses by negatively regulating T-cell responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity [33,34]. Interestingly, tumors hijack the mechanisms of these immune checkpoints as protection against anti-tumor immune responses elicited by CD4+ and CD8+ T-cells in order to establish an immunosuppressive TME, hindering their eradication [35]. Consequently, restroring T-cell effector fuctions via Immune Checkpoint Blockade (ICB) had become an established modality of immunotherapy [36]. ICB employs Immune-Checkpoint Inhibitors (ICIs) such as ipilimumab, nivolumab, and pembrolizumab to block these co-inhibitory receptors on T-cells in order to release the potential of the anti-tumor immune response. Although reversing immune checkpoint inhibitor pathways have generated much excitement, these approaches still lack absolute success [37]. As a matter of fact, ICB was only effective in a minority of patients with heavily mutated tumors [38]. Additionally, managing immunotherapy-related severe adverse effects remains a challenge [39]. In fact, these immunotherpautic agents brought a new wave of unique toxicity profiles that are distinct from the toxicities of other cancer therapies (because they activate a broad range of immune cells) [40]. In particular, ICB induced novel toxicities that were labelled as immune-related Adverse Events (irAEs) including colitis, hepatitis, myositis, pneumonitis, endocrinopathies, kidney injury, and skin toxicities [41].  Moreover, a growing body of basic science, translational, and clinical evidence now suggests that myocarditis may be the tip of the iceberg in terms of cardiac irAEs, with ICI-induced acceleration of AtheroSclerotic CardioVascular Disease (ASCVD) contributing significantly to vascular toxicity in the long term [42]. Furthermore, CAR T-cell therapy induce potentially severe or even life-threatening immune-related toxicities including Cytokine Release Syndrome (CRS), Hemophagocytic LymphoHistiocytosis (HLH) and/or Macrophage Activation Syndrome (MAS) which often manifests following resolution of CRS (recently termed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, IEC-HS), and the life-threatening albeit commonly occurring Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) [43]. CAR-T-associated neurotoxicity also include recent reports of encephalitis caused by reactivation of Human HerpesVirus 6 (HHV-6) in patients receiving CAR T-cells [44,45,46]. Moreover, prolonged and persistent cytopenias, recently termed Immune Effector Cell-Associated Hematological Toxicity (ICAHT), leading to increased risk of infections, life-threatening bleeding, and long-term transfusion support have become a major therapeutic challenge added to the bill of CAR T-cell therapy [47,48,49]. One major limitation for broader applicability of CAR T-cell therapies is that more than 50% of patients who respond to CAR T-cell therapies eventually relapse [50]. For instance, more than half of patients with high-grade lymphomas will progress and require additional therapy after CAR T-cell therapy. Failure after CAR T-cell therapy is caused by a variety of factors that can be divided into 3 broad categories: tumor intrinsic factors, other host factors, and inadequacies of the CAR T-cells [51]. To sum up, paucity of therapeutic targets, toxicities related to CAR T-cell therapy, and resistance to CAR T-cell therapy are the main challenges that hinder widespread commercialization of CAR T-cell therapy [52]. In a similar vein, although BiTEs- the concept of which dates to the 1960s when Alfred Nisonoff envisioned the potential of replacing one of the two identical antigen binding arms with a different antigen binding specificity [53] -have been proved to be efficient in many R/R hematologic malignancies, a subset of patients still have no response to BiTEs [54]. Often overlooked, the financial toxicities of these agents can negatively affect patient outcomes and quality of life. In particular, CAR-engineered immune cells continue to remain a complex and extremely expensive technology hindering affordability and access to CAR T-cell therapy [55,56].

PD-1, programmed cell death protein-1; PD-L1, programmed cell death protein-ligand 1; CTLA-4, cytotoxic T-lymphocyte–associated antigen 4; Mac, macrophage; CBP35, carbohydrate binding protein 35; LBP, a non-integrin laminin binding protein in macrophages; TIM-3, T cell immunoglobulin mucin-3; UAT, urate transporter; LAG-3, lymphocyte-activation gene 3; LSECtin, liver sinusoidal endothelial cell lectin; FGL-1, Fibrinogen-like protein 1; α-syn, α-synuclein fibrils; TIGIT, T cell immunoreceptor with Ig and ITIM domains; WUCAM, Washington University Cell Adhesion Molecule; VSTM3, V-set and transmembrane domain-containing protein 3; PVR, the poliovirus receptor; Necl, nectin-like molecule; PVRL2, Poliovirus receptor-related 2.
Note: ¹ Galectin-3 was found to interact with two clinically-relevant immune checkpoint molecules: CTLA-4 and LAG3. In the first case, galectin-3 associated to complex branched N-glycans, increasing CTLA-4 retention on the cell surface and downregulating TCR signal strength. On the other hand, galectin-3 has been found to promote CD8+ T cell dysfunction by engaging LAG-3.
² Major histocompatibility complex (MHC) class II on antigen-presenting cells (APCs) is the canonical LAG-3 ligand.
³ TIGIT is a co-inhibitory molecule and a novel member of the CD28 family (was first identified in 2009). Similar to LAG3 and TIM3, belongs to the immunoglobulin superfamily.
⁴ Nectins and nectin-like (Necl) molecules are a family of 9 adhesion molecules that belong to the immunoglobulin superfamily. They play a key role in different biological processes such as cell polarity, proliferation, differentiation and migration in epithelial, endothelial, immune and nervous systems. Some of these molecules also function as receptors for poliovirus and herpes simplex viruses.

Table 1: The main T cell exhaustion markers and their ligands

Despite that B-cell Acute Lymphoblastic Leukemia (B-ALL) has an excellent prognosis in children with long-term survival of 80%–90% [57], the event-free survival for pediatric B-ALL has plateaued over the past decade leaving approximately 25% of patients with R/R disease [58]. Patients with R/R B-ALL especially in the post-transplant setting continue to have a dismal prognosis [59]. On the other hand, there is no light at the end of the tunnel where multiple myeloma (MM) exists. MM - a B-cell malignancy and the second most frequently diagnosed hematologic cancer- remains incurable despite significant advances in treatment due to the lack of appropriate antigen(s) for targeted-cell killing [60]. Despite many new approved drugs and numerous combinations of these agents, including the use of proteasome inhibitors, immunomodulatory drugs, and mAbs, resistance eventually ensues and most patients will die from their disease [61]. Currently, CD19 and the B-Cell Maturation Antigen (BCMA) are the most common targets for CAR T-cell therapy in B-cell malignancies. Although initial CAR T-cell activity shows promising response rates, especially in Diffuse Large B-Cell Lymphoma (DLBCL) and B-ALL, only a minority of patients attain long-term disease remission [62]. For instance, resistance or relapse after CD19-directed CAR T-cell therapy occurs in the majority of patients within 1–2 years [63]. Approximately, 30%–60% of patients relapse after CD19-directed CAR T-cell therapy, and 10 to 20% of relapsed patients experience CD19-negative relapse [64]. Although CAR T-cell therapy is considered the game-changer for B-cell malignancies, their use for other malignancies is still challenging [65]. For instance, CAR T-cell therapy does not work for Acute Myeloid Leukemia (AML), mainly due to high incidence of CRS and relatively poor clinical efficacy [66]. In addition, generating autologous CAR T-cells from patients with T-cell malignancies has been particularly problematic and quite challenging [67,68]. So far, none of the immunotherapeutic modalitis can completely replace allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) in spite of the remarkable advances in immunotherapy for blood cancers over the past decades [69]. It is worth noting that allo-HSCT is one of the oldest forms of cancer immunotherapy for hematologic malignancies. However, this approach was prohibitive as the first choice in any treatment strategy due to its inherent risks of Transplantation-Related Mortality (TRM) and morbidity including the development of Graft-versus-Host Disease (GvHD) [70]. On the other hand, achieving and maintaining CR before allo-HSCT is paramount, but it remains a significant hurdle. Moreover, viral pathogens are a significant source of morbidity and mortality after allo-HSCT [71]. Indeed, many post-HSCT patients eventually enter a deadly vicious cycle of GvHD and viral infections. In addition, invasive fungal infections are a major cause of morbidity and mortality among HSCT recipients [72]. Strikingly, HSCT still often fails due to the relapse of the malignancy [73]. Please note that details on hematologic malignancies (Figure-1) are beyond the scope of this article but are summarized elsewhere [74].

Figure 1: Overview of hematologic malignancies.
CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; DLBCL, diffuse large B-cell lymphoma; MCL, mantle cell lymphoma; FL, follicular lymphoma; WM, Waldenström macroglobulinemia; HCL, hairy cell leukemia; SBLPN, splenic B-cell lymphoma/leukemia with prominent nucleoli; Ph, Philadelphia chromosome; CML, chronic myeloid leukemia; PMF, primary myelofibrosis; PV, polycythemia vera; ET, essential thrombocythemia; JMML, juvenile myelomonocytic leukemia; CNL, chronic neutrophilic leukemia; CEL, chronic eosinophilic leukemia; MPN-NOS, myeloproliferative neoplasm, not otherwise specified; MDS/MPN, myelodysplastic syndrome/myeloproliferative neoplasm. NB. JMML is categorized under myeloproliferative neoplasms according to 5th edition of the WHO classification of Haematolymphoid Tumours.

Despite that glycans (carbohydrates) have been overlooked in drug discovery strategies for many centuries, glycobiology has recently come to the forefront of biomolecular and biomedical research. Every cell in our body is virtually surrounded by a dense coating of complex and diverse glycans (the “glycocalyx”) which have essential role in the interaction between cells and the microenvironment [75]. Glycosylation, the process by which sugars are post-translationally added to proteins or lipids with the aid of certain enzymes, is an integral part of cellular function governing innumerable biological processes. Glycans bind several Pattern Recognition Receptors (PRRs) on immune cells, the so-called lectins.

Lectins are a diverse group of non-antibody Glycan-Binding Proteins (GBPs) that are found abundantly in nature (the other group of GBPs, sulfated Glycosaminoglycan (GAG)-binding proteins is not addressed here) [76]. Through binding to lectins, glycans regulate key biological processes including protein folding, cell adhesion, molecular trafficking and clearance, receptor activation, signal transduction, and endocytosis [77]. As glycosylation is universal in living organisms, aberrant glycosylation as a result of changes in glycan synthetic pathways is also a universal feature of tumor cells with fundamental role in oncogenesis and metastasis [78].

In fact, aberrant glycosylation is causally associated with the acquisition of all hallmarks of cancer [79]. “Hallmarks of Cancer”– a phrase originally coined by Doug Hanahan and Bob Weinberg –define a set of cell biological processes frequently dysregulated in tumors, contributing to their progression [80]. In particular, changes in sialic acid glycosylation allow cancers to participate in ‘immune evasion’ by engaging inhibitory sialic-acid-binding immunoglobulin-like lectins (Siglecs) on the surface of immune cells [81,82].

Noteworthily, sialic acid residues terminate cell-surface glycans and serve as Self-Associated Molecular Patterns (SAMPs). Similar to the Cytotoxic T-Lymphocyte–Associated Antigen 4 (CTLA-4) and programmed cell death protein-1 (PD-1) checkpoint proteins, Siglecs contain signaling domains capable of preventing immune activation which render overexpressing tumor-associated sialoglycans (sialic acid-containing glycans) a strategy employed by tumors to evade the immune system. Hence, there is compelling evidence supporting that the sialoglycan-Siglec axis have become a powerful and appealing target for cancer immunotherapy [83,84]. Moreover, glycans expressed in malignant cells, known as Tumor-Associated Carbohydrate Antigens (TACAs), are abundantly and uniquely expressed on tumor cells. TACAs are strongly implicated in malignant transformation and tumor progression. As cancer-specific antigens, TACAs serve as ideal targets for the development of novel modalities in cancer diagnostics and therapeutics [85,86].

During the past decade, remarkable progress has been achieved in the application of glycan-targeting therapies for solid tumors. Glycan-targeting approaches include monoclonal antibodies (mAbs) [87], Antibody-Drug Conjugates (ADCs) [88,89], bispecific antibodies [90,91,92,93], vaccination [94,95,96,97,98,99], and recently lectibodies [100,101]. Lectibody is a chimeric protein composed of lectin and crystallizable fragment (Fc) of IgG antibody that can act as a carbohydrate-targeting antibody [102]. Two anti-glycan mAbs have been approved by the United States Food and Drug Administration (FDA or US FDA) for high-risk neuroblastoma (dinutuximab/Unituxin and naxitamab/nyelza) [103]. Despite that CAR T-cell therapy has enjoyed success in the clinic for liquid tumors (blood cancers), the broad effectiveness of CAR T-cell therapy for treating solid tumors remains disappointing [104,105]. In fact, the discrepancy in success of CAR T-cell therapy between liquid and solid tumors is attributable to the CAR T-cell’s ability to physically enter and penetrate deeply into the TME [106]. Surprisingly, however, targeting glycopeptides by CAR T-cells in solid tumors have yielded promising results [107,108], providing compelling evidence for the enormous potential of glycan-targeting therapies to rejuvenate the field of tumor immunology. For example, GD2 CAR-T phase I trial showed feasibility and safety in osteosarcoma and neuroblastoma [109]. In spite of the irrefutable potential of glycan-targeting therapies in solid tumors, this field remains underexplored in liquid tumors. Undoubtedly, the expression of TACAs occurs in most hematological malignancies and their roles were reviewed in the literature [110,111]. Recent research has shown that changes in the glycosylation profile of T-cells and B-cells have been related to the development of leukemias including B-ALL, B-Cell Chronic Lymphocytic leukemia (B-CLL), T-cell Acute Lymphoblastic Leukemia (T-ALL) [112]. Unfortunately, glycobiology remains a very little commented subject in the classrooms of different biomedical courses as it is an emerging field within immunology [113]. This case is even worse when it comes to clinicians. Most hematologists are generally unaware of glycobiology. Therefore, the aim of this review is to make hematologists familiar with TACAs and immune lectins within the context of hematologic oncology while focusing on mechanistic pathways that link lectin pattern recognition and potential tumor targeting strategies.

Untangling the Sweet Mechanics of Liquid Tumors

Aberrant glycosylation: the sugar sculpting art of cancer 

Glycobiology is the study of glycans and their recognition by motif-specific glycan-binding proteins or lectins [114]. Carbohydrates (glycans) are among the four major classes of biomolecules (besides nucleic acids, proteins, and lipids). Glycans are ubiquitous on the surface of all living cells and also found on most secreted proteins. Glycans are essential structures that play remarkable roles in the immune system, cellular signaling, and host-microbe interactions. Glycans usually exist as glycoconjugates (glycoproteins, proteoglycans and glycolipids), rather than existing in a free state [115]. Nearly all initial interactions of a cell with neighbouring cell(s), cell matrix, other proteins, or with a pathogen are mediated mainly by glycans [116]. Glycans are sensed by glycan binding receptors expressed on immune cells, such as C-type Lectin Receptors (CLRs) and Siglecs that respond to specific glycan signatures by triggering tolerogenic or immunogenic signaling pathways [117]. Noteworthily, the term “glycomics” refers to studies that profile the glycome, while the term “glycome” describes the complete repertoire of glycans and glycoconjugates that cells produce under specified conditions of time, space, and environment [118]. On the other hand, the term “glycoproteomics” describes this glycome as it appears on the cellular proteome. Correspondingly, glycoproteomics determines which sites on each glycoprotein of a cell are glycosylated and ideally includes the identification and quantitation of the heterogeneous glycan structures at each site [119]. Strikingly, the cell-surface glycome, termed glycocalyx, is a dense layer combining glycoproteins and sugar moieties on cell surfaces, can extend more than 30 nm from the plasma membrane. It is worth noting that all cells in the bone marrow (BM) are surrounded by a glycocalyx which regulates such cell-cell and cell-matrix interactions [120]. The process by which oligosaccharides are added to the proteins or lipids to form glycoconjugates in the Endoplasmic Reticulum (ER) and Golgi apparatus is called glycosylation. Noteworthily, the Golgi apparatus is home to a multitude of glycosyltransferases, glycosidases, and nucleotide sugar transporters that function together to complete the synthesis of glycans from founding sugars covalently attached to protein or lipid in the ER [121]. Mechanistically, the primary mechanisms by which glycans can be linked to proteins or lipids are N-glycosylation and O-glycosylation, where glycans are added sequentially to the amide group of an Asparagine (Asn) residue and the hydroxyl oxygen of Serine/Threonine (Ser/Thr) residues respectively. Although N-and O-glycans are often found on the same proteins, they differ strongly in their compositions and biosynthesis [122]. It is important to note that in most of the cases both N-and O-linked glycans are capped at the terminal position with sialic acids, Lewis blood group related antigens or ABO (H) blood group determinants. Furthermore, glycosylation of proteins and lipids in mammals is essential for embryogenesis and the development of all tissues [123]. Not surprisingly, glycosylation is the most common Post-Translational Modification (PTM), dynamically shaping the glycans on proteins and lipids traveling through the secretory pathway, and comprising an extensive glycocalyx on the cell surface [124]. The three major classes of cell surface glycoconjugates execute numerous functions, including fine-tuning of molecular interactions, intra- and intercellular communications, and immune modulation [125,126]. Mechanistically, glycosylation modification of proteins or lipids provides a vital stabilizing force for proteins within their microenvironment, thereby modulating their biological functions [127]. For instance, glycans added to proteins play a pivotal role in protein folding, oligomerization, quality control, sorting, and transport [128]. These glycoproteins represent the majority of the key molecules involved in the innate and adaptive immune response [129]. Dysregulated (aberrant) glycosylation plays a crucial role in disease processes, including oncology. The aberrant glycosylation occurs because of cellular and metabolic variations leading to variant expressions of integrated glycans [130]. Aberrant glycosylation results in various functional changes of glycoproteins which confer the unique characteristic phenotypes associated with cancer cells. In a similar vein, glycolipids play critical roles in various aspects of tumorigenesis as well as considered promising immunotherapeutic targets for cancer therapy [131]. Strikingly, cancer cells have adapted to the selection pressure exerted by the immune system through harnessing their glycome to create an immunosuppressive environment that results ultimately in immune evasion. This is called aberrant glycosylation, a universal feature of cancer cells found in essentially all tumor cells [132]. Not surprisingly, emerging evidence highlighted that altered glycans play key roles in tumorigenesis and tumor progression. Moreover, glycosylation is currently a subject of much interest for its potential role in metastasis, which is responsible for 90% of cancer-related deaths [133].

Noteworthily, the glycocalyx drives the interplay between cancer cells and the TME, a complex scaffold of Extracellular Matrix (ECM) and various cell types. Stiffening of the ECM, likely due directly to specific changes in glycan content/composition of the tumors, is common in cancer. Cancer cells sense and transduce mechanical stiffness of the ECM into intracellular responses by a process called mechanotransduction, which promotes aberrant cell functions and contributes to cancer progression. A wide range of glycans are also involved in cancer cell mechanotransduction [134]. Cumulative evidence shows that cell surface glycosylation expression pattern is altered on cancer cells, leading to aberrant expression of cancer-associated glycans - also called Tumor-Associated Carbohydrate Antigens (TACAs)-serving as biomarkers of cancer progression as well as ideal targets for novel anti-tumor immunotherapy approaches [135]. TACAs are created by the collaborative activities of glycosyltransferases, glycosidases, nucleotide-sugar transporters, sulfotransferases, and glycan-bearing protein/lipid scaffolds [136]. In addition, TACAs contribute to shape unique glycocodes with distinct mechanisms of immunosuppression through their interactions with endogenous lectin receptors expressed by immune cells such as the C-type selectins and the S-type galectins; and therefore, defining the glyco-code of each tumor is essential for understanding its immune evasion potential [137]. In this context, the best characterized TACAs in hematologic malignancies are shown in Figure 2.

Figure 2:The expression of cancer-associated glycans and glycoproteins in hematologic malignancies
Glycoproteins require specific glycopeptide epitope (such as sLeX on a core 2 residue with nearby sulfated tyrosine on PSGL-1 and TF on MUC1) to bind their partner lectins. Therefore, these glycoproteins and their glycopeptide epitopes represent target antigens that can be harnessed to treat hematologic malignancies.
CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; MM, multiple myeloma; ALL, acute lymphoblastic leukemia; BL, Burkitt's lymphoma; AML, acute myeloid leukemia; HL, Hodgkin lymphoma; DLBCL, diffuse large B-cell lymphoma; CSPG4, chondroitin sulfate proteoglycan 4.

Cancer-associated changes in glycosylation

Genetic and epigenetic modifications of glycan biosynthesis result in the characteristic pattern of cancer-associated glycosylation. The most-widely occurring cancer-associated changes in glycosylation are sialylation, fucosylation, O glycan truncation, and N-and O linked glycan branching [138,139]. Mechanistically, TACAs arise either from [140] incomplete synthesis (originating from truncated structures - more common in early carcinogenesis) [141,142] or neo-synthesis processes (de novo synthesis of neoantigens is more frequent in advanced stages of several cancers) [143]. Noteworthily, these changes affect how the immune system responds to malignant cell transformations [144]. Strikingly, aberrant glycosylation is under the regulation of glycosylation enzymes- glycosyltransferases and glycosidases. After N-glycosylation or O-glycosylation, a series of fucosylation and sialylation are required to complete the assembly. The addition of sialic acid or fucose moieties to the N-linked or O-linked glycoproteins, the so-called glycan capping [145,146], is one of the most frequently occurring modifications in cancer [147]. It worth noting that these terminal variations have produced highly antigenic epitopes with species-specific functions. Aberrant sialylation and fucosylation are closely associated with the development and progression of cancer [148]. In particular, aberrant sialylation is one of the most common changes in glycosylation occurring in cancer that have been shown to correlate with tumor progression and metastasis [149]. In this vein, the most widely occurring changes in glycosylation linked to cancer progression include an enhancement of N-glycan branching due to increased activity of the glycosyltransferase β1,6-N-acetylglucosaminyltransferase-5 (GnT-5 or MGAT5), and alterations to α2-6 sialylated N-glycans - a modification driven by the sialyltransferase enzyme β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) [150]. Despite that alterations in glycosylation have emerged as a significant player in malignant transformation and tumor progression [151], cancer-associated glycans and glycosyltransferases remain largely unexplored as potential biomarkers or therapeutic targets [152].

N-linked glycosylation

N-glycosylation allows tumor cells to resist cell death induced by chemotherapy [153]. Biochemically, N-Glycans consist of N-Acetylglucosamine (GlcNAc) attached by a β1-glycosidic linkage to the nitrogen atom of the amino group of Asn (N) at the consensus glycosylation motif Asn-X-Ser/Thr (in which X denotes any amino acid except for proline). These Asn-linked glycoconjugates contain a GlcNAc₂ mannose (Man)₃ core, to which a variable number of other monosaccha-rides can be added or removed. Additions determine whether the final structure is classed as a high-mannose N-glycan (in which only mannose residues are attached to the core), a hybrid N-glycan (addition of galactose or fucose residues along with mannose in the Golgi complex) or a complex N-glycan (addition of GlcNAc further extends the chain in the Golgi complex) [154]. Noteworthily, one of the major factors conferring structural variation of N-glycans is the variable number of GlcNAc branches [155]. Branching of the nascent N-linked glycan chain is initiated in the medial Golgi through a family of enzymes known as N-acetylglucosaminyltranferases (GnTs), which are encoded by MGAT genes. Strikingly, the degree of branching of N-linked glycans is dictated by the collective action of GnTs and ranges from hybrid glycans with a single antenna to complex N-glycans with bi-, tri-, or tetra-antennary structures [156]. In this context, GnT-5/MGAT5 (encoded by the GnT-5/MGAT5 gene) is a mammalian glycosyltransferase involved in complex N-glycan formation [157]. Mechanistically, GnT-5/MGAT5 was found to be critical for the formation of tri- and tetra- antennary complex N-linked glycans by catalyzing the attachment of β1,6-GlcNac to an α1,6-linked mannose residue of the nascent N-glycan core as it passes through medial Golgi [158]. Strikingly, GnT- 5/MGAT5 is one of the most characterized cancer-associated glycosyltransferases that has long been implicated in tumor progression and metastasis [159,160]. A growing body of evidence suggests that malignant transformation is associated with increased expression of β1,6GlcNAc-branched N-glycans, resulting from enhanced expression of GnT-5/MGAT5, which is regulated by the RAS/RAF/MAPK signaling pathway in cancer [161]. Strikingly, GnT-5-dependent N-glycans play important roles in cell-cell and cell-matrix adhesion. Mechanistically, GnT- 5 functionally modifies cell adhesion molecules, including the Epithelial cadherin (E-cadherin), and growth factor receptors, thereby promoting cancer cell migration and proliferation [162]. Within this context, the degree of N-glycan branching of several Receptor Tyrosine Kinases (RTKs) contributes to its capability to induce or arrest cellular proliferation [163,164]. Not surprisingly, a wide variety of malignant tumors exhibits a high expression of MGAT5, and this characteristic has also been related to the acquisition of malignant potential [165]. In this vein, the increased expression of the β1,6-GlcNAc–branched N-glycans has been linked to tumor aggressiveness and poor prognosis in several cancers involving the breast, colon, oesophagus, stomach, liver, brain (gliomas) and endometrium [166,167,168]. Reciprocally, loss of MGAT5 has been associated with decreased tumor growth in multiple cancers both in vitro and in vivo, including Colorectal cancer (CRC) [169,170], breast cancer [171,172], nasopharyngeal carcinoma [173], lung adenocarcinoma [174], Hepatocellular Carcinoma (HCC) [175,176,177], and gastric cancer [178]. Recently, Hollander et al., demonstrated that loss of MGAT5 results in tumor clearance that is dependent on T-cells and Dendritic Cells (DCs), with Natural Killer (NK) cells playing an early role. Using a panel of murine Pancreatic Ductal Adenocarcinoma (PDAC) clonal cell lines that recapitulate the immune heterogeneity of PDAC, they found that MGAT5 is required for tumor growth in vivo but not in vitro which provides support for MGAT5 as a target for clinical translation [179].

Furthermore, the β1-6-GlcNAc branch initiated by GnT-5/ MGAT5 can be further elongated by the addition of galactose to the initiating GlcNAc to produce the ubiquitous building block Galβ1-4GlcNAc, referred to as a type-2 N-acetyllactosamine or “LacNAc” sequence. The sequential addition of LacNAc disaccharides gives tandem repeats known as poly-N-acetyllactosamine (poly-LacNAc). This poly-LacNAc structure is a ligand for galectins (a family of conserved carbohydrate-binding proteins involved in a plethora of cellular activities), which bind to the carbohydrate structures of the receptors forming a lattice, which regulates their turnover on the plasma membrane, usually potentiating the signaling downstream [180,181]. Mechanistically, the ability of receptors to bind galectins is critically dependent on the degree of branching of their N-linked chains, in particular on the presence of the β1,6-branch synthesized by GnT-5/MGAT5. The functional role of branched N-glycosylation in cancer was later shown to be dependent on galectin binding and thereby altering the phenotype of the cell [182]. For instance, evidence revealed that the galectin lattice formation due to interaction with the β1,6 attached poly-LacNAc N-linked glycans on the T-Cell Receptor (TCR) forms a spatial barrier that restricts spontaneous clustering of TCR in the absence of T cell-specific antigen [183,184]. In addition to regulating TCR clustering and signaling, further studies revealed that GnT-5/MGAT5 is also critical to maintaining surface expression/retention of the inhibitory receptor CTLA-4/CD152 (cytotoxic T-lymphocyte–associated antigen 4) on T-cells due to enhanced CTLA-4-galectin lattice formation [185]. Not surprisingly, GnT-5/MGAT5 is a therapeutic target for cancer and immune-related diseases [186]. Notably, complex and hybrid N-glycans may also carry a “bisecting” GlcNAc residue that is attached to the β-Man of the core by MGAT3 or GnT-3 (encoded by the MGAT3 gene) [187]. Despite being involved in the suppression of cancer metastasis (contrary to GnT-5/MGAT5), bisecting GlcNAc are the commonest N-glycan alterations described in hematological malignancies. Mechanistically, it was suggested that this reduced metastasis was caused by functional alterations of E-cadherin by bisecting GlcNAc modification and suppression of Epithelial–Mesenchymal Transition (EMT) by MGAT3 [188,189]. Intriguingly, MGAT3, the enzyme responsible for the addition of bisecting GlcNAc residues, has been reported to be elevated in MM and chronic myeloid leukemia (CML) patients in blast crisis [190]. The experimental upregulation of MGAT3 in K562 leukemia cells enhanced resistance to NK cell’s cytotoxicity and spleen colonization [191], via regulation of cell recognition by bisecting GlcNAc moieties [192].

Receptor Tyrosine Kinases (RTKs)

Importantly, glycosylation adds a second level of proliferation regulation by mediating growth factor receptor activation and structural alterations [193]. Within this context, one of the major cell surface protein groups implicated in the cellular signal transduction include glycoprotein Receptors with Tyrosine Kinase activity (RTKs) which control essential cellular processes like cell division, metabolism, differentiation, motility and death, ensuring homeostasis of the cell and the human body [194]. RTKs are important N-linked glycosylated proteins expressed by both immune cells as well as cancer cells which get activated by receptor modification and impact key features of metastasis like migration, invasion etc. Intriguingly, many RTKs linked to proliferation and survival are governed through glycosylation, including the Platelet-Derived Growth Factor (PDGF), Fibroblast Growth Factor Receptor (FGFR), Epidermal Growth Factor Receptor (EGFR), v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2, also known as human epidermal growth factor receptor 2 (HER2) and neu), mesenchymal-epithelial transition factor (Met or c-Met), or insuliN-like growth factor receptor (IGFR, also known as CD221; IGFIR;IGF1R) [195]. These RTKs are all known to be regulated by cancer-associated glycans [196], glycosyltransferases [197], and proteoglycans (major constituents of the extracellular matrices as well as the cell surfaces and basement membranes) [198,199]. Not surprisingly, aberrant RTKs are associated with nearly all human cancers and RTKs constitute molecular targets for numerous selective therapies [200,201]. Typical RTK is composed of a highly glycosylated N-terminal extracellular ligand binding domain (ectodomain) which initiates receptor signaling upon binding to either soluble or membrane-embedded ligands, a single helical transmembrane domain and an intracellular tyrosine kinase domain [202]. Nevertheless, there is a large diversity found within their extracellular domains, which enables the recognition of structurally different ligands [203,204,205]. The diversity of extracellular domain structures allows for coupling of many unique signaling inputs to intracellular tyrosine phosphorylation but, importantly, this diversity is further increased by the fact that multiple ligands can typically interact with the same receptor [206]. On the other hand, the transmembrane domain plays a key role in the formation and stabilisation of the dimer of the receptor chains [207]. Notably, one of the factors that contribute to the diversity of RTK activities are post-translational modifications, including glycosylation of RTKs and their ligands. This posttranslational modification may directly modulate RTK stability, ligand binding and cellular trafficking, deciding about strength, specificity and duration of the signals [208]. Not surprisingly, the glycosylation pattern of RTKs’ extracellular ligand binding domains may largely differ between normal and cancer cells. Strikingly, a highly abundant RTK-attached glycans constitute multiple binding sites for galectins. Mechanistically, interaction of receptors with galectins and their consequent entrapment in a lattice promotes retention of receptors at the cell surface [209]. Intriguingly, most of RTKs are subjected to extensive site-specific N-and O-glycosylation. Depending on the receptor type and structure of the extracellular domain there is a great diversity in the number and type of glycan structures attached to RTKs. For instance, N Fujitani et al., found that the extracellular domain of ErbB2 possesses eight sequons, suggesting that ErbB2 is highly N-glycosylated. In addition to N-glycans, this study proposed a specific structure for the O-glycans that ErbB2 may possess, although the exact site was not definitively determined [210]. In a similar vein, A. Gedaj et al., showed that all FGFRs are heavily N-glycosylated in numerous positions within their extracellular domains; while 15 out of 22 members of their ligands (FGFs) are N-glycosylated and few FGFs are O- glycosylated [211]. Strikingly, N-linked glycosylation is a critical step in the maturation of transmembrane RTKs and plays a central role in RTK ligand binding, trafficking, and stability. For instance, the extracellular domain of the Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) is highly N-glycosylated and these N-linked glycans play a significant role in stabilizing the VEGFR-2 extracellular domain and may also influence ligand and drug binding to VEGFR2 [212]. In addition, the degree of N-glycan branching of several RTKs contributes to its capability to induce or arrest cellular proliferation. In this vein, it has been shown that growthpromoting receptors such as EGFR, IGFR and FGFR exhibit a higher number of N-linked chains than inhibitory receptors like Transforming Growth Factor Beta (TGFβ) Receptor (TGFBR) and CTLA-4 [213,214]. Noteworthily, EGFR is the most studied RTK and one of the four members of the Human Epidermal Growth Factor Receptor (HER) family receptors (EGFR/HER1/ erbB1, HER2/erbB2, HER3/erbB3, and HER4/erbB4) [215]. Using the EGFR as a prototypical RTK, studies have shown that N-glycosylation is required for EGFR trafficking, efficient ligand binding, and receptor activation [216,217,218,219,220]. Mechanistically, N-glycosylation critically determines membrane interactions and structural arrangement of the ligand-binding EGFR ectodomain [221]. However, both fucosylation and sialylation of EGFR N-linked glycans has been shown to impact ligand binding and signaling [222]. As a result, it has been proposed that disruption of N-linked glycosylation could lead to a decreased expression level of mature RTKs and thus interfere with the RTK signaling cascades in cancers [223]. Showcasing this, Contessa et al., found that nanomolar concentrations of the N-linked glycosylation inhibitor, tunicamycin (Tm), reduced the tumor cell protein levels of four RTKs (EGFR, ErbB2, ErbB3 and IGF1R) that contribute to tumor cell proliferation and survival. Mechanistically, disrupting this synthetic process impairs RTK signaling in tumor cells through retention of the receptors in the ER/Golgi compartments resulting in a reduction in RTK expression levels [224]. Not surprisingly, there is growing interest in exploring glycans found on RTKs as promising therapeutic targets, aiming to overcome drug resistance and advance cancer treatment strategies [225].

The N-glycan-dependent quality control mechanism of glycoprotein folding

Newly made membrane and secreted proteins undergo quality control as they enter the ER lume to ensure proper protein folding and function. Proper protein folding and localization depend on efficient glycosylation, without which cells may respond to the presence of unfolded protein by pathways that lead to apoptosis. Mechanistically, N-glycosylation directly affects the folding of glycoproteins by altering their biophysical properties [226]. As part of a quality control system for protein folding, N-glycans are recognized by two homologous molecular chaperones in the ER: Calnexin (CNX) and Calreticulin (CALR) [227]. Both CALR and CNX are Ca⁺⁺-binding L-type lectins that bind to monoglucosylated, high-mannose-type glycans. This binding keeps misfolded glycoproteins in the ER until they are correctly folded [228]. Interestingly, mutations in CALR were added to the 2016 version of the World Health Organization (WHO) classification for myeloproliferative neoplasms (MPNs) [229]. CALR mutations are the second most frequent mutation after JAK2 in essential thrombocythemia (ET) (25% of patients) and primary myelofibrosis (PMF) (35% of patients). Surprisingly, CALR-mutant patients often have a more benign clinical course than those patients Janus kinase 2 (JAK2) V617F-mutated disease [230]. Trials using INCA033989 (a fully human monoclonal IgG1 antibody that selectively binds to mutated CALR) in CALR-mutated ET and/or patients with MF are expected soon [231]. Mechanistically, mutant CALR stabilizes the transmembranous MPL (myeloproliferative leukemia protein, also known as the Thrombopoietin Receptor or TPO-R), resulting in ligand-independent activation of MPL and downstream JAK– STAT signaling pathway activation [232,233,234,235,236,237]. Strikingly, mutations in CALR drive overstimulation of MPL signaling in a glycosylation-dependent manner. Specifically, mutant CALR binds the immature N-glycan form of the MPL in the ER. Subsequently, the complex is transported to the cell membrane, where MPL is constitutively activated by mutant CALR, leading to cytokine-independent proliferation and development of MPNs [238]. Interestingly, elucidating the mechanisms by which mutant CALR causes MPN paved the path for immunological targeting of this cell surface neoantigen (e.g., by mAbs) resulting in the abrogation of JAK–STAT signaling indicating successful inhibition of MPL activation [239]. It is worth noting that accumulation of UN- or mis I folded proteins in the ER lumen induce ER stress that triggers the Unfolded Protein Response (UPR) which either restores the balance of protein homeostasis or induces apoptosis of the damaged cell if it is deemed unrepairable [240]. Strikingly, UPR signaling is often dysregulated in leukemias and represents a novel therapeutic target [241]. Normally, the wild-type FLT3 (FLT3-WT) is synthesized as a 130 kDa underglycosylated species but then is folded in the ER and exported to the Golgi apparatus, where it is glycosylated to form a 150 kDa protein prior to translocation to the cell surface [242,243]. By contrast, the FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD), which confers a strong negative prognosis in AML patients, is mostly retained in the ER as the underglycosylated 130 kDa species due to impaired glycosylation and folding [244]. Mechanistically, Marcotegui et al., showed for the first time that the protein SET (I2PP2A/TAF-Iβ) is involved in the transport of FLT3-WT to the membrane; however, FLT3- ITD mutation impairs the SET/FLT3 binding, leading to its retention in the ER. Interestingly, results also showed that the FLT3 inhibitor midostaurin promotes FLT3 transport to the cytoplasmic membrane in part by facilitating FLT3 binding to SET [245]. In this vein, the therapeutic induction of ER stress/ UPR-mediated apoptosis has emerged as a promising avenue for the treatment of FLT3-ITD positive AML. In particular, 2-Deoxy- D-glucose (2-DG), tunicamycin and fluvastatin have has antiproliferative and pro-apoptotic effects on FLT3-ITD positive AML by inhibiting FLT3-ITD N-glycosylation which keep FLT3-ITD in the ER [246,247,248]. Intriguingly, 2-DG displays a significant anti-leukemic activity in AML with FLT3-ITD or KIT D816V mutations, opening a new therapeutic window in a subset of AML with mutated RTKs [249]. Furthermore, 2-DG and Tm have also produced ER stress/UPR-mediated apoptosis in patients with T-ALL and B-ALL [250,251]. Noteworthily, 2-DG, because of its structural similarity to mannose, inhibits N-glycosylation via competition with endogenous D-mannose and misincorporation into the precursors of N-glycosylation [252]. Interestingly, Li et al., revealed that the combining 2-DG with imatinib resulted in a synergistic inhibition against CML cells, including those with T315I mutation that were otherwise resistant to imatinib alone [253]. Recently, Toshihiko et al., demonstrated that 2-DG-treated CAR T-cells augmented the efficacy of CAR T-cell therapy. Mechanistically, 2-DG causes CAR T-cells to resist immunosuppression in the TME via decreasing N-glycosylation of the heavily glycosylated immune-inhibitory receptors (PD-1 and CTLA-4) on T-cells and thereby decreasing their affinities to their ligands released from tumor cells (PD-L1 and CD80/ CD86 respectively) [254]. In a similar vein, treatment with 2-DG prevented T-cells from binding to galectin-3 (a potent tumor antigen associated with T-cell anergy), resulting in suppression of galectin-3-induced T-cell apoptosis. Notably, human T-cells treated with 2-DG upregulated the NK-specific transcription factors TOX2 and EOMES, thereby acquiring NK cell properties, including surface marker expression and high levels of cytotoxic molecules, such as perforin/granzyme leading to enhanced cytotoxicity to tumor cells. Mechanistically, 2-DG-treated T-cells expressed higher levels of surface interleukin-2 receptor (IL-2R) with increased sensitivity to IL-2, resulting in greater secretion of perforin and granzyme. Moreover, cancer cells expressing Natural Killer Group 2D (NKG2D) ligands were killed more effectively by 2DG-treated T- cells than by control T-cells [255]. Furthermore, it is important to note that N-glycosylation also directly regulates T-cell function by altering the threshold of TCR activation [256]. The TCR, in association with CD8, recognizes a complex formed by antigenic peptides and class I MHC [257,258]. The association between the TCR and CD8 depends on reduced TCR glycosylation. Conversely, interaction of galectin-3 with N-glycan impairs TCR clustering and decreases T-cell activation by restraining lateral TCR movement [259]. Therefore, by disruption of this interaction, 2-DG promotes TCR clustering with CD8 while decreasing the threshold for activation, resulting in a hyperimmune response.

O-linked glycosylation

Mucin-type O-glycans (O-GalNAc glycans) are a class of glycans initiated with N-acetylgalactosamine (GalNAc) α-linked primarily to Ser/Thr residues within glycoproteins and often extended or branched by sugars or saccharides. Mucin-type O-glycans were first observed on mucins. Mucins, the biomolecular components of mucus, are large and heavily glycosylated proteins (glycoproteins) that form a thick physical barrier at all tissue-air interfaces, forming a first line of defense against pathogens [260]. As they are carrying the greatest number of O-GalNAc glycans, mucins constitue an important source of glycopeptides in cancer. However, most secretory and membrane-bound proteins also receive O-GalNAc glycans, which are important in regulating many biological processes. Notably, mucin-type O-glycosylation is present at the interface between cells where it has important roles in cellular communication [261]. Cancers express altered mucintype O-glycans. Physiologically, these tumor O-glycans comprise (1) oncofetal antigens, which are rare in normal adult tissue but expressed embryonically; (2) neoantigens, which are novel structures not appreciably expressed either embryonically or in normal tissues; and (3) altered levels of normal antigens. Normal adult tissues do not express oncofetal or neoantigens which makes them ideal for targeted diagnostics and therapeutics. Chemically, tumor O-glycans consist of both relatively small-sized, truncated O-glycans including the truncated glycans Tn, sialyl Tn, and T as well as the extended glycans ABO(H) and sialylated Lewis antigens on poly-LacNAc. Truncated O-glycans tend to be tumorspecific, or only found in tumors but not in normal cells, while altered terminal structures tend to be tumor-associated, with distinct changes noted in tumors but the structures themselves present in some normal tissues. Importantly, alterations in O-glycan terminal structures are also observed on N-glycans and glycolipids, in contrast to truncated O-glycans found only on O-glycans.

Biochemistry

Mucin-type O-glycosylation initiates with transfer of N-acetylgalactosamine (GalNAc) from UDP-GalNAc to Ser/ Thr in a glycoprotein via an α-linkage to form GalNAcα1- Ser/ Thr, which is also recognized as the Tn antigen [262]. This reaction is catalyzed by a family of enzymes called polypeptide GalNAc-transferases (ppGalNAcTs or GalNAc-Ts), consisting of 20 members in humans. Importantly, alterations in GalNAc-Ts expression patterns are associated with malignant transformation. In addition, some GalNAc-Ts have been have been characterized as diagnostic and prognostic markers [263,264,265,266,267,268 ,269,270,271,272,273]. Tn is a truncated form of the elongated cell surface O-glycan. The hypoglycosylation leading to Tn may occur when the enzyme responsible for O-glycan Elongation-Tsynthase- or its associated chaperone-Cosmc-becomes functionally inhibited [274]. Expression the Tn antigen may itself be involved in driving oncogenesis as its expression directly induces oncogenic features, including dysplastic morphology, increased invasive properties, and decreased cell-cell and cell-matrix adhesion [275,276,277,278,279]. The Tn antigen has been shown to modulate immune cell interactions through interactions with the macrophage galactose C-type lectin (MGL) [280,281,282,283]. Intriguingly, G. Libisch et al., found a Tn antigen expression in most of the CLL patients studied when the VVB4 lectin was used. Gene expression analysis showed for the first time that GALNT11, which encodes the polypeptide N-acetylgalactosaminyltransferase 11 (GalNAc-T11), is overexpressed in 96% of B-CLL cells when compared to normal B- cells. GalNAc-T11mRNA was also present in Jurkat (leukemic T-cell lines) and T-cells, but was not detected in Daudi cells (leukemic B-cell lines). Because GalNAc-T11 is present in B–CLL cells and in T-cells from healthy donors, while its expression is very low in normal B-cells, it seems that GalNAc-T11 could be included with ZAP-70 among markers normally expressed by T-cells, which are aberrantly expressed by B–CLL cells. These results suggest that GALNT11 constitutes a new molecular marker for CLL capable to act as surrogate marker for unmutated IGHV genes with poor prognosis, and is associated with the progression status of the disease and LPL expression. In this vein, since there is not a perfect concordance between ZAP-70, LPL and the IGHV mutational status, further work is needed to better define whether the addition of GALNT11 expression could improve prognosis assessment in CLL patients [284]. Synthesis of Tn antigen is typically followed by transfer of galactose (Gal), GlcNAc, or GalNAc to the Tn antigen to form core O-glycan structures 1–8. Cores 5–8 are rare structures, whereas cores 1–4 are common. Alternatively, the Tn antigen can be sialylated by N-acetylgalactosamine α2,6 sialyltransferase 1 (ST6GALNAC1), which generates sialyl Tn antigen on O-glycans and prevents LacNAc formation on O-glycans (which inhibits galectin-3 binding; see below). Core 1 (Galβ1–3-GalNAcα-Ser/Thr) is synthesized by the T-synthase (Core 1 β3-galactosyltransferase, C1GalT1), which transfers Gal from UDP-Gal to Tn in the cis- and medial-Golgi. Core 1 is the most common O-GalNAc glycan that forms the core of many longer, more complex structures. It is antigenic and is also named the Thomsen-Friedenreich (TF or T) antigen. The oncofetal TF antigen can also be expressed in various pathologies, such as cancer, as well as on activated B-cells during a germinal center reaction. Indeed, the TF carbohydrate antigen is a pancarcinoma antigen highly expressed by about 90% of all human carcinomas (normally covered by more expanded glycosylation and sialylation in normal epithelium) [285]. Notably, MUC1 is amongst the few proteins known to express unsubstituted TF antigen [286,287]. Interestingly, core 1 is classically defined as a type 3 chain (Galβ1–3GalNAc-R) and can serve as a platform for blood group antigens, such as H, A, and B antigens, as well as for O-glycan-specific modifications such as the Cad (Sda) antigen, which is also found on extended core 2, 3, and 4 structures. Core 1–4 structures are often extended to form various structures. Core 1- and core 2-based structures are ubiquitously expressed. On the other hand, core 3 is restricted to the GI tract in humans (most often found on mucins in the colon) and core 4 is formed from core 3 by the addition of GlcNAc to GalNAc with a β1,6- linkage. Strikingly, cores 3, 4, and their extended structures are generally not observed in cancer cell lines [288,289]. In fact, the expression of the core 3 is down-regulated in colon cancer tissues and colon cancer cell lines, while the expression of core 1 and core 2 is up-regulated [290,291].

Extended core 1: Core 1 can be further converted to core 2 O-glycan by one of three β1,6-N-acetylglucosaminyltransferases (Core 2 GlcNAc Transferases, C2GnT1–3) that add GlcNAc to the core 1 O-glycan [292]. Core 2 GlcNAc Transferases have recently been shown to be necessary for proper function of the innate immune system, since core 2 O-glycans are essential for selectin ligand biosynthesis [293]. C2GnT1 (GCNT1) and C2GnT3 (GCNT4) only modify core 1 to form core 2 structures, whereas C2GnT2 (GCNT3) can also modify core 3 to form core 4 structure. Noteworthy, the expression of C2GnT1 (GCNT1) is associated with the progression of several cancers [294]. Notably, core 1 is most often sialylated by ST3GAL1 (responsible for adding α2,3-linked sialic acids to substrates to generate α-2,3 sialylated core 1 O-glycans) and/or ST6GALNAC 1-4 to form mono or disialyl core 1. In addition, core 1 can be elongated or extended by Core 1 β3-N-acetylglucoaminyltransferase (Core 1 GnT) by transferring GlcNAc from UDP-GlcNAc to form extended core 1, GlcNAcβ1–3Galβ1–3GalNAcα1-Ser/Thr. This can be further modified by other glycosyltransferases to form sulfated sLeX structures on extended core 1. Noteworthily, extended core 1 Oglycans are expressed by specialized endothelial cells within the high endothelial venules (HEVs) and these also contain sulfated GlcNAc residues within the sLeX motif (6-sulfo-sLeX)[295].

Extended core 2: Extended core 2 are quite common and mediated by alternating activity of β4GalTs and β3GnTs, which form polyLacNAc chains based on type 2, repeats (3Galβ1–4GlcNAcβ1-)n. These structures can be expressed as linear (nonbranched) chains, branched by I-branching β-1,6-Nacetylglucosaminyltransferase (Gcnt2, also known as β1–6GnT-I or IGnT) to form branched structures, and/or modified by fucosyltransferases, ST3Gal- and ST6Gal-sialyltransferases, sulfotransferases, etc., to form various blood group antigens as well as Lewis, sialyl Lewis, and sulfo sialyl Lewis structures. Intriguingly, these linear and branched polyLacNAc chains represent the fetal i antigen and the adult “I-branches” (I-blood group antigen) respectively. The blood group I antigen is present on adult human erythrocytes and many mucins, whereas the i antigen is expressed on fetal human erythrocytes. Interestingly, the blood group I antigen is found in N-glycans and glycolipids, in addition to O-glycans [296].

Mucins

Mucins-barrier glycoproteins that form mucus and other gellike secretions -are densely O-glycosylated glycoproteins that play critical roles in a host of healthy and disease-driven biological functions [297]. Glycoproteomics and prediction algorithms identified mucin-type O-glycans on ~83% of proteins entering the ER–Golgi secretory apparatus, including many non-mucin proteins [298]. This indicated that mucin-type O-glycans are ubiquitous [299]. In particular, mucins are dominant carriers of cancer-associated carbohydrates and they are able to amplify changes at the surface of the cancer cells [300]. Mechanistically, cancer-associated mucins form nanoscale material barriers that resist attack by immune cells, including NK cells and CAR T-cells. Interestingly, glycocalyx editing with mucin degrading enzymes including sialidases (enzymes that cleave terminal sialic acids from glycoproteins and glycolipids) and mucinases (enzymes capable of degrading mucins) can overcome the glycocalyx armour of cancer cells [301]. Not surprisingly, mucins have long been a target of interest in oncology [302]. Within this context, the mucins MUC1, MUC2, MUC4, and MUC16 are mucins associated with cancer progression [303], whereas MUC1 (also known as CA 15-3, the most widely used serum marker in breast cancer), MUC4, and MUC16 (also known as Ovarian cancer-related tumor marker CA125) serve as circulating biomarkers of different types of cancer [304]. MUC1/ CD227 (also known as episialin, EMA, PEM, CA15–3 and DF3) is a large and heavily glycosylated transmembrane mucin protein expressed at the apical surface of epithelial cells at mucosal surfaces including the breast tissue, airways, and gastrointestinal tract where it has a barrier function against bacterial invasion [305]. MUC1 is the most intensively studied transmembrane protein of the mucin family [306]. Interestingly, MUC1 was the first identified transmembrane mucin in many solid tumors and hematopoietic cancers, which is often upregulated and aberrantly glycosylated, making it a potential therapeutic target for cancer immunotherapy [307]. MUC1 consists of a large extracellular domain, a transmembrane region and a short cytoplasmic domain/tail. The MUC1 extracellular domain contains variable numbers of 20-amino acid tandem repeat peptides (VNTR) that are heavily glycosylated (up to 50% of the MUC1 molecular weight) with complex O-linked mucin type glycans [308]. Physiologically, MUC1 forms a protective barrier through the mucosal surface and protects the cells from extreme environmental conditions. Pathologically, MUC1 loses polarity upon malignant transformation and becomes overexpressed and aberrantly glycosylated, revealing an immunogenic region of tandem repeats of 20 residues. The novel MUC1 glycoforms that arise carry shortened glycan moieties: Tn (GalNAc), T (Galβ1, 3GalNAc), sT (NeuAcα2, 3Galβ1, and 3GalNAc), and sTn (NeuAcα2, 6GalNAc) [309,310]. In this vein, numerous studies have shown that interactions of sialylated glycans of tumor-associated MUC1 with Siglecs promote tumor immune escape, ultimately affecting the body’s antitumor immunity [311,312]. Not surprisingly, MUC1 is commonly overexpressed (up to 10-fold) in various epithelial adenocarcinomas including lung, liver, colon, breast, pancreatic, and ovarian cancer where it has intracellular signaling functions and plays a significant role in cancer development [313]. Strikingly, MUC1 interacts with various cellular proteins involved in regulating proliferation, adhesion and immunomodulation of epithelial cancers. One such interaction is with EGFR, an important regulator of epithelial cell growth and survival in normal and cancerous tissues [314]. In this context, MUC1 is associated with EGFR in epithelial cancers such as breast, pancreatic, endometrial and lung. Of particular interest, EGFR mutations are the most common oncogenic drivers in Non-Small- Cell Lung Cancer (NSCLC) [315]. EGFR exists normally in an inactive conformation but its activity is increased in neoplasia. Interestingly, Engel et al., showed for the first time that MUC1 increases expression and signaling of EGFR which indicates that MUC1-EGFR co-expression is associated with increased cellular proliferation in human tumors, highlighting the importance of MUC1-driven EGFR expression and signaling [316]. Not surprisingly, EGFR has become a principal therapeutic target for cancer treatment. Examples of established EGFR inhibitors include the reversible inhibitors (gefitinib and erlotinib) and the irreversible inhibitors (dacomitinib, osimertinib, and poziotinib) which have become prominent and effective treatments for EGFR-driven NSCLC [317]. Furthermore, MUC1 promotes the migration and invasion of a variety of cancers and can lead to the emergence of drug resistance during cancer therapy [318]. MUC1 appears in many hematological malignancies, including T-cell and B-cell lymphomas and myelomas [319], and is a potential prognostic marker and therapeutic target for several types of Non- Hodgkin Lymphomas (NHLs) [320,321].

Fucosylation

The process of transferring fucose from GDP-fucose to their substrates catalyzed by fucosyltransferases is referred to as fucosylation. Fucosylation is a nonextendable modification and generally subdivided into terminal fucosylation (giving rise to specific Lewis blood-group antigens) and core fucosylation. Pathologically, abnormal fucosylation is associated with various cancers. The process of fucosylation relies on a series of Fucosyltransferases (FUT1-11). Fucosyltransferase 8 (FUT8) is the most important FUT in mammalian cells, which catalyzes the transfer of GDP-β-L-fucose to the N-sugar chain of Asn in the adjacent GlcNAc residues to form core fucose (Fuc) [322]. Interestingly, FUT8 is the only enzyme responsible for core fucosylation of N-glycans during glycoprotein biosynthesis [323]. Core fucosylation directly modulates the biological activity of glycoproteins, such as the bioactivities of several tyrosine kinase receptors [324,325], and the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC) of IgG antibodies [326]. For instance, the expression of FUT8 is important for the biological functions of TGF-β receptors, keeping in mind that TGF-β is a major inducer of EMT in different cell types, and TGF-β-mediated EMT is thought to contribute to tumour cell spread and metastasis [327]. As a matter of fact, over 90% of N-glycans from human serum IgG are core fucosylated [328]. Intriguingly, removal of core Fuc from therapeutic IgG was found to raise its ADCC by about 100-fold [329], and this approach is now used clinically. In addition, FUT8 has been reported as a responsible factor for the synthesis of cancer-associated N-glycan structures [330,331]. Not surprisingly, enhanced core fucosylation is often associated with cancer progression [332]. Showcasing this, the upregulated expression of FUT8 has been reported in several cancers, including lung cancer [333], prostate cancer [334], HCC (a major form of liver cancer) [335,336,337], and CRC, for which FUT8 was discovered as a prognostic marker in patients with stage II and III CRC, demonstrating that FUT8 is involved in biological tumor characteristics and patient outcomes [338]. Besides, the upregulated expression of FUT8 increased the fucosylation of the TGFBR and its downstream signaling, promoting the breast cancer tissue invasion and metastasis [339]. It is worth noting that core fucosylation of alpha-fetoprotein (AFP-L3 fraction) due to the upregulation of FUT8 in HCC cells is a FDA-approved serum tumor marker for the specific diagnosis of HCC [340,341]. Among the family of FUTs, there are six α-1,3-FUTs that specifically modify terminal lactosaminyl glycans, the last step in biosynthesis of Lewis X antigens (i.e. ‘‘Lewis X’’ (Le^X; CD15) and ‘‘sialyl Lewis X’’ (sLe^X; CD15s) [342]. Notably, upregulated α-1,3- FUTs activity, resulting in the overexpression of Le^X and sLe^X determinants, is etiologic in several human diseases including cancer and autoimmune conditions [343,344,345,346,347,348]. The principal α-1,3-FUTs that mediate sLe^X creation (the canonical binding determinant for selectins) are FUT6 and FUT7 [349], with FUT9 dominating Le^X synthesis [350]. FUT7, which makes only sLe^X, was significantly upregulated in AML M5. FUT7 fucosylation has also been reported to play a crucial role in the generation of PSGL-1 (also called CD162), expressed on the surface of most leukocytes, is a counter-receptor for P-selectin [351]. Interestingly, adult T-cell leukemia/lymphoma (ATLL) cell lines strongly express sLe^X which is dependent on FUT7 [352,353,354,355]. Mechanistically, HTLV-1, the etiologic agent of ATLL, encodes a transcriptional activator protein (TAX) which regulates the FUT7 gene [356].

O-GlcNAcylation 

O-GlcNAcylation was discovered in the 1980s, overturning the previously accepted dogma that protein glycosylation did not occur in the nucleus and cytoplasm. Indeed, it has been shown that O-GlcNAcylation plays an important role in a broad range of cellular functions by modifying nuclear, cytosolic, and mitochondrial proteins. Chemically, O-GlcNAcylation is a ubiquitous form of intracellular glycosylation [357], that results when the amino-sugar GlcNAc made in the hexosamine biosynthetic pathway (HBP) is covalently attached to Ser/Thr residues in thousands of proteins in the nucleus, cytoplasm and mitochondria by the glycosyltransferase O-linked GlcNAc transferase (OGT). O-GlcNAcylation is an abundant protein post-translational modification. There are known to be at least 8000 human proteins modified and regulated by this dynamic sugar modification of proteins [358]. 

Furthermore, O-GlcNAcylation has extensive crosstalk with phosphorylation both at the site level on polypeptides and by modifying many kinases. O-GlcNAcylation also cross-talks to regulate ubiquitination, methylation, acetylation, and other post-translational modifications [359]. Like phosphorylation and ubquitination, O-GlcNAcylation regulates many different cellular processes [360]. Intriguingly, O-GlcNAcylation appears to be particularly abundant on proteins involved in signaling, stress responses, and energy metabolism [361]. Not surprisingly, O-GlcNAcylation is highly sensitive to nutrient availability and stress, and levels of protein O-GlcNAcylation change in response to nutrient availability and metabolic, oxidative, and proteotoxic stress [362]. In addition, O-GlcNAcylation plays a role in a broad range of biological processes, such as transcription, translation, enzyme activity, cell division, protein localization and degradation [363]. Intriguingly, the dynamic and reversible modification of nuclear and cytoplasmic proteins by O-GlcNAcylation has the potential to significantly alter immune responses. For instance, O-GlcNAcylation is essential in the process of lymphocyte activation in both B- and T-lymphocytes [364]. Therefore, understanding the precise molecular mechanisms involving O-GlcNAcylation in the immune system is critical for developing new therapeutics for immune and inflammatory diseases, as well as for lymphoid and myeloid cancers [365]. The donor sugar for O-GlcNAcylation, uridine-diphosphate N-acetylglucosamine (UDP-GlcNAc), is synthesized from glucose through the HBP. The recycling of O-GlcNAc on proteins is mediated by two highly conserved and ubiquitous nucleocytoplasmic enzymes that carry out its addition and removal. OGT is the only enzyme capable of adding O-GlcNAc to proteins, and O-GlcNAcase (OGA) removes it [366]. By the way, the UDP-GlcNAc metabolite is a common substrate for O-GlcNAcylation and for N-glycan branching. Furthermore, despite being a type of protein glycosylation, O-GlcNAc is very different from other N-linked and O-linked glycans [367]. Firstly, O-GlcNAcylation occurs mostly on intracellular proteins (confined to nucleocytoplasmic and mitochondrial compartments). Secondly, O-GlcNAc moiety remains as a monosaccharide (i.e., not generally elongated or modified). Thirdly, in contrast to the dynamic nuclear/ cytoplasmic O-GlcNAcylation, O-glycans in the secretory pathway are stable throughout the life of the glycoprotein (unless acted upon by glycosidases, such as sialidases/neuraminidases derived from pathogens during infection). Cancer cells, including lymphoid and myeloid malignancies, display enhanced levels of O-GlcNAcylation, likely due to their relatively higher levels of glucose flux and altered growth kinetics [368]. Within this context, evidence indicates that the HBP, specifically through O-GlcNAcylation, helps fuel cancer cell metabolism, growth, survival, and spread [369]. Cancer cells also show increased OGT expression, which increases O-GlcNAcylation and promotes cancer cell proliferation and resistance to chemotherapy [370]. Consequently, elevated O-GlcNAcylation (hyper-OGlcNAcylation) is a signature of cancer-specific metabolism and linked to various hallmarks of cancer, including cancer cell proliferation, survival, invasion, and metastasis; energy metabolism; and epigenetics [371]. Not surprisingly, hyper-OGlcNAcylation has emerged as a new hallmark of cancer [372]. Hyper-O-GlcNAcylation is a general feature of several cancers including breast, prostate, pancreas, lung and colon [373] but also occur in hematologic malignancies. In this context, MM cells resistant to bortezomib were found to have higher concentration of UDP-GlcNAc and OGT levels as compared to bortezomibsensitive cells [374]. Y. Jin et al., showed for the first time an increased GlcNAcylation in the BM of MM patients, and by using AANL6, a mutant Agrocybe aegerita GlcNAc-specific lectin, found that the combined expression of two secreted glycoproteins (FBLN1and DKK1) can be used as a novel clinical biomarker for the diagnosis of MM [375]. These findings suggest that increased GlcNAcylation is associated with the pathogenesis of MM, which could potentially have therapeutic implications. Converesly, CLL cells express high levels of O-GlcNAcylated proteins, such as p53, c-Myc, and Akt but are surprisingly associated with with an indolent clinical behaviour [376]. This observation is somewhat paradoxical as important signaling pathways in CLL including the NFκB, MEK/ERK, PI3K/AKT/mTOR, JAK, and Notch pathways can all be affected by O-GlcNAcylation. Reasons for the inverse correlation between total O-GlcNAcylated protein levels and clinical course in CLL are still unclear [377].

Aberrant sialylation

In 1957, a 9-carbon acidic (based around an alpha-keto acid core) monosaccharide was designated “sialic acid” and is one of the ten monosaccharides used in the enzymatic process of glycosylation in mammals [378]. Sialic acids are predominantly found at the non-reducing end of N-linked and O-linked glycans attached to glycoproteins or glycolipids. Fundamentally, all jawed vertebrates have cell-surface glycans that terminate with sialic acid residues [379]. Intriguingly, these sialic acids have a pivotal role in infection (viruses, bacteria, protozoa) [380]. The sialic acid family consists of nearly 50 members that are derivatives of N-acetylneuraminic acid (Neu5Ac), N-glycolylneuraminic acid (Neu5Gc), and 3-deoxy-dglycero- d-galacto-non-2-ulopyranosonic acid (deaminoneuraminic acid; 2-keto-3-deoxy-d-glycero-d-galacto-nononic acid; Kdn). However, Neu5Ac is the most abundant sialic acid in humans [381] and serves as a key marker of self in glycan-coding sequences [382]. Sialylation is defined as the terminal addition of sialic acid to the oligosaccharide and glycoconjugates. This enzymatic process is tightly regulated by Sialyltransferases (STs) and sialidases/ Neuraminidases (NEUs) in normal cells. There are twenty Golgi localised sialyltransferases with different substrate and linkage specificity in charge of protein and lipid sialylation in humans [383]. On the other hand, only 4 mammalian sialidases (NEU1, NEU2, NEU3 and NEU4) release sialic acids from sialylated glycoconjugates [384]. However, the accumulation of sialylation in tumors is due to the high expression of sialyltransferases and the altered expression of sialidases [385]. Not surprisingly, both sialyltransferase inhibitors [386,387] and sialidases have emerged as novel anticancer therapeutic interventions in cancer [388]. Based on the category of glycosidic linkage, sialylation can be classified into three types: α2-3-, α2-6-, and α2-8-sialylation [389]. As sialic acids decorate the majority of mammalian glycans at the cell surface and in the extracellular space, they are considered as SAMPs [390,391]. Physiologically, sialic acids confer a negative charge to the sialylated glycoproteins and glycolipids that contribute to glycoconjugates’ biophysical and physiological functions. Pathologically, sialylation modifies the conformation of essential proteins to promote cancer cell proliferation, invasion, and migration. Recently, Tharp et al., found that the physical properties of the microenvironment influence immune surveillance via compositional and topological dynamics of the sialic acid-containing glycocalyx [392]. Aberrant sialylation is the most critical change in glycosylation occurring in cancer. It is not only a consequence of tumor transformation but is a driver of the malignant phenotype. Therefore, aberrant sialylation is an established hallmark of several types of cancer. The alterations of sialic acid processing have two main implications: 

1. Hypersialylation: a general upregulation of sialoglycans (sialylated glycans) on cell surfaces of tumors. Sialoglycans including sialyl-Tn (sTn), sialyl-T (sT) and sialyl-Lewis antigens, polysialic acid, and gangliosides are often exploited as tumorassociated antigens (i.e., as markers for cancer detection and monitoring) [393,394]. By interaction with sialoglycan-binding lectins, including Siglecs and selectins, hypersialylation has been linked to immune evasion, drug resistance, tumor invasiveness, and metastasis. In fact, the ability of tumor cells to metastasise correlates with total sialic acid levels [395]. 

2. An increased introduction of the non-human sialic acid Neu5Gc instead of Neu5Ac into cell surface glycans.

Sialyltransferases

Hypersialylation is the result of dysregulated expression of sialyltransferases. Sialyltransferases are categorized under inverting glycosyltransferases, i.e., enzymes which invert the stereochemistry of the donor’s anomeric bond (α → β). In the Golgi apparatus, these enzymes catalyze the transfer of sialic acid moiety from an activated sugar nucleotide donor, that is, CMP-Neu5Ac (Cytosine 5′-monophosphate N-acetylneuraminic acid) to non-reducing positions of acceptors such as galactose, N-Acetyl galactosamine, and other sialic acid residues [396]. Altered sialyltransferase expression leads to the formation of specific sialylated structures [397]. Notably, an increase in α2,6 sialylation on N-glycans (the addition of α2,6-linked sialic acids onto subterminal galactose residues of lactosaminic chains of N-glycans), a modification driven by ST6GAL1 is a common change in tumor cell glycosylation [398]. In this vein, Munkley et al., have recently revealed the mechanisms underlying how ST6GAL1-mediated aberrant sialylation of N-glycans promotes prostate cancer bone metastasis and provided proof-of-concept data to show that sialic acid blockade can inhibit bone metastasis which is a common, debilitating and incurable consequence of advanced prostate cancer [399]. In addition, the α2-3 sialyltransferases (ST3GAL) family transfer sialic acid residue in an α2,3-linkage to terminal Gal residues present on glycolipids or glycoproteins resulting in the synthesis of gangliosides (ST3GAL2 and 5), the tumor-associated sialyl-T (sT) (ST3GAL1) and the sialylated derivatives of Lewis antigens (sialyl-Lewis X [sLeX]), sialyl-Lewis A [sLeA]). Within this context, ST3GAL3, ST3GAL4 and ST3GAL6 are involved in the synthesis of sLeX, while sLeA (also known as carbohydrate antigen 19-9 [CA19-9] which serves as a tumor marker) is predominantly generated by ST3GAL3 [400]. Sialyltransferases are implicated in cancer and immune suppression by synthesizing sialoglycans, which act as ligands for Siglec receptors [401]. Moreover, the tumor markers sLeA and sLeX are ligands for selectins [402]. Since selectins are one of the main mediators of leukocytes trafficking, it is conceivable that sLeA and sLeX are potentially involved in the malignant behavior of cancer cells as they both promote tumor metastasis [403,404]. In a similar vein, the dysregulated expression of the sialyltransferase ST3GAL6, a key regulator of selectin ligand synthesis, is implicated in disease progression and survival in MM [405]. Mechanistically, the upregulation of sialyltransferases promotes tumor metastasis via several routes, including stimulating tumor invasion and migration through integrin-mediated processes, inhibiting Fas-mediated apoptosis and evading immunosurveillance [406]. For instance, ST6GAL1–mediated sialylation of EGFR influences integrin-dependent adhesion and cell mechanics across different cancer cell lines [407]. Interestingly, studies have shown that inhibition of sialyltransferases reduces cancer metastasis [408,409]. Furthermore, sialyltransferases can promote resistance to chemotherapy and radiotherapy [410,411,412,413]. Within this context, the expression of sialylated antigens on the cell surface is emerging as an important feature of cancer cell Multidrug resistance (MDR). MDR is a well-established cause of chemotherapy failure and disease progression in patients with leukemia [414]. The efflux of cytotoxic drugs mediated by transporter proteins belonging to the ATP binding cassette (ABC) family is the "classical MDR" pathway [415]. In fact, MDR is conventionally regarded as the consequence of overexpression of ABC transporters in tumor cells which lead to lower intracellular drug accumulation and hence reduce cellular toxicity of chemotherapeutic agents [416]. While there is strong evidence that activation of the phosphoinositide 3 kinase (PI3K)/Akt signaling network plays a significant role in rendering AML blasts drug resistant, data confirmed the correlation of the ST6GAL1-mediated PI3K/Akt signaling pathway with multidrug resistance [417,418]. It has been reported that the PI3K/Akt signaling enhances drug efflux by transporter proteins belonging to the ATP binding cassette (ABC) family in order to maintain MDR of tumor cells [419]. In fact, MDR is conventionally regarded as the consequence of overexpression of ABC transporters which lead to lower intracellular drug accumulation and hence reduce cellular toxicity of chemotherapeutic agents. The two main members of ABC transporters frequently used as markers to screen MDR patients clinically are P-glycoprotein (P-gp) and MDR-associated protein 1 (MRP1). While the membrane glycoprotein P-gp actively pumps cytotoxic agents out of cells and decreases their intracellular concentration [420], MRP1 plays an active role in protecting cells by its ability to efflux a vast array of drugs to sub-lethal levels [421]. Interestingly, ST6GAL1 was found to increase the expression of P-gp and MRP1 through PI3K/Akt pathway, thereby mediating MDR of leukemia cells [422]. Table-2 delineates the role of several sialyltransferases in hematologic malignancies.

Note: ¹ Patients with high MYC expression are also likely to have high ST6GALNAC4 expression. High ST6GALNAC4 expression, among all sialyltransferases, is the strongest predictor of adverse patient outcomes in BL, DLBCL, CLL, and T-ALL, which notably all have high MYC activity.
² This glycotope is recognized by Siglec-7. CD162/PSGL-1 and CD45 are the major carriers of disialyl-T antigen on CLL B-cells.
³ The primary role of ST3GAL1 is to catalyze the attachment of Neu5Ac and Thomsen-Friedenreich (TF) antigens (Gal-β1,3-GalNAc), resulting in the production of sialylated TF antigens.
⁴ ST3GAL4 contributes to the synthesis of either Siglec-9 or selectin ligands. ST3GAL4 is one of three sialyltransferases attaching sialic acid to N-glycans via α2,3 linkage in mammals (along ST3GAL3 and ST3GAL6), with ST3GAL4 likely to play a major role.
⁵ Based on ST3GAL4/FUT7 expression, M3 cells may also be a subtype with elevated sLeX levels.
⁶ This is the first report of a mammalian α2,8-sialyltransferase that preferentially sialylates O-glycans.
⁷ This study indicated that α-2,8-sialyltransferases involved in the development of MDR of CML cells probably through ST8SIA4 regulating the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling and the expression of P-gp.
⁸ ST3GAL6 contributes to formation of Siglec and Selectin ligands.
BL, Burkitt lymphoma; DLBCL, diffuse large B-cell lymphoma; CLL, chronic lymphocytic lymphoma; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; MM, multiple myeloma; HTLV-1, the human lymphotropic virus type 1; MDR, multidrug resistance.

Table 2: The role of selected sialyltransferases in hematologic malignancies

Hypersialylation

Hypersialylation is an established hallmark of several cancers where it is directly proportional to their metastatic phenotype and poor prognosis [438,439]. Tumor cells commonly mask themselves by hypersialylating their surface glycans leading to the enhanced expression of sialoglycans, which through the interaction with Siglec receptors, leads to immune evasion by shutting down anti-tumor responses. Mechanistically, sialoglycans on the hypersialylated cancer cell surface bind to Siglecs on immune cells to mediate immunosuppression, inhibiting the cytotoxicity of NK cells and the activation of T-cells, and inducing a Tumor-Associated Macrophage (TAM) phenotype, to promote continued tumour growth. Hypersialylation can also induce immune evasion by interference with the complement system via a “molecular cloaking” mechanism mediated by Factor H sequestration and dampening of the complement-mediated cell lysis and opsonisation [440]. Conversely, sialic acid deficient tumors showed a favorable T-cell landscape characterized by enhanced CD8+ T-cells and decreased CD4+ regulatory T-cells (Tregs). Noteworthily, CD8+ T-cells are end effectors of cancer immunity; and hence, most forms of effective cancer immunotherapy involve CD8+ T-cell effector function [441]. Not surprisingly, targeting sialic acids synergizes with immunotherapy and can improve survival [442]. Additionally, sialic acids represent critical determinants of selectin ligands, which contribute to extravasation of immune cells to target organs and sites [443].

The expression of selectin ligands (SleA/X) on cancer cells seems to correlate with metastatic phenotype [444,445,446,447,448]. For instance, E-selectin ligands expressed on MM cells played a role in BM homing and possibly retention of the malignant cells in the BM [449,450]. In addition to the generation of selectin ligands, sialylation plays other roles in MM. In 2020, Natoni et al., reported that desialylation (removal of sialoglycans from cancer cells) by using a global sialyltransferase inhibitor (3Fax-Neu5Ac) impaired maturation of the α4 integrin which affected its affinity for its counter-receptor as well as greatly reduced the ability of MM cells to interact with E-selectins, Vascular Cell Adhesion Molecule 1 (VCAM-1) and Mucosal vascular Addressin Cell Adhesion Molecule 1 (MADCAM-1), which altered adhesion and rolling mediated by α4β1 and α4β7 integrins respectively. Intriguingly, 3Fax-Neu5Ac reduced the tumor burden, increased survival and showed a synergistic therapeutic effect in combination with bortezomib [451]. Noteworthily, both α4β7 and α4β1 integrins are highly expressed on MM cells [452,453], and the expression levels of β7 integrin (2 known members: α4β7 and αEβ7) on MM cells correlates with poor survival in MM patients [454]. Therefore, inhibiting sialylation may represent a new therapeutic strategy to overcome BM-mediated chemoresistance [455].

O-Acetylation of sialic acids

Sialic acids found in mammalian organisms vary in their substituent at C5, which in Neu5Ac is an acetylated amino group, in Neu5Gc a glycolylated amino group, and in Kdn a hydroxyl group [456]. The 5-amino group can also exist in nature in non- N-acylated form, giving rise to neuraminic acid (Neu). Neu5Ac, Neu5Gc, Kdn, and Neu collectively comprise the four ‘core’ Sia molecules. The four ‘core’ Sia molecules can also undergo various natural modifications that impart a second level of diversity as they sometimes carry one or more additional substitutions on the hydroxyl groups at C-4, C-7, C-8, and C-9 (O-acetyl, O-methyl, O-sulfate, or O-lactyl groups). The most common modification of sialic acids is O-acetylation preferentially occurring at the C-4, C-7, C-8, and C-9 hydroxyl groups of the nonulosonic acid and sialic acid backbone. However, because O-acetyl esters from C-7 and C-8 positions are known to spontaneously migrate to C-9 even under physiological conditions, O-acetylation at C-9 is considered the most common biologically occurring modification. For example, N-acetyl-9-O-acetylneuraminic acid (Neu5Ac9Ac) is the most frequent postsynthetic change in humans [457].

Neu5Gc

The two most common forms of sialic acid found in mammalian cells are Neu5Ac and its hydroxylated derivative, Neu5Gc. The enzyme cytidine monophospho-Neu5Ac hydroxylase (Cmah, encoded by the CMAH gene) catalyzes the convertion of Neu5Ac to Neu5Gc. However, in humans this enzyme is inactive [458]. In spite of this, Neu5Gc-sialoconjugates have been detected in human tissues, particularly in tumors with dietary incorporation of Neu5Gc being currently the most accepted hypothesis [459,460]. The higher proliferation of malignant cells would explain the preferential expression of these antigens in tumors [461], also favored by the increased uptake under hypoxic conditions [462,463]. Neu5Gc expression in human tissues enhances inflammation due to an anti-Neu5Gc immune response, which can potentially influence inflammation-induced cancer and cancer-associated inflammation [464]. Since expression of Neu5Gc in humans being associated with malignant transformation, therefore, Neu5Gc is an attractive target for cancer immunotherapy [465].

O-linked modifications in epidermal growth factor repeats on Notch

Two unusual forms of O-linked glycans, namely, O-fucose and O-glucose, were initially described on the Epidermal Growth Factor (EGF) repeats of mouse Notch1 [466]. Later, evidence unraveled that the signaling pathway best known to be regulated by O-glycans on EGF repeats is the Notch signaling pathway. Intriguingly, Notch is an evolutionary-conserved signaling system that regulates cell fate decisions through local cell–cell interactions [467]. In this context, the available evidence indicates that Notch signaling has important roles in many cellular processes, including differentiation, proliferation, apoptosis, and stem cell maintenance [468]. Not surprisingly, dysregulation of Notch signaling leads to various human diseases, including cancer [469]. Interestingly, investigations into Notch predate the identification of almost all signal transduction systems [470]. The principal understanding of the interaction between Notch and its ligands was obtained through studies on Drosophila, flies with Notch-ed wing phenotype as originally observed by John S. Dexter in 1914 [471]. However, the discovery of human-specific Notch genes has led to a better understanding of Notch signaling in development and diseases and will continue to stimulate further research in the future [472]. Notch is a large (>300 kDa) cell-surface receptor that contains 36 tandem EGF repeats comprising the majority of its extracellular domain (ECD). However, the Notch pathway core components include Notch receptors, Delta/Serrate/LAG-2 (DSL) family of ligands, the Notch receptor proteases Adam and γ-secretase, and the nuclear effector CSL (CBF1/RBPjκ/Su(H)/ Lag-1) [473,474]. Both Notch receptors and the DSL Notch ligands are Type-I transmembrane glycoproteins with a single transmembrane domain. Mammals have four Notch receptors (Notch1–4), all consist of an ECD or NECD (Notch extracellular domain) and an intracellular domain (ICD) or NICD (Notch intracellular domain); and two types of canonical DSL (Delta/ Serrate/LAG-2 family) ligands: three Delta-like ligands (DLL1, DLL3, and DLL4), and two Serrate-like (Jagged) ligands (JAG1 and JAG2). The ECD of DSL ligands contain a conserved N-terminal DSL domain and several EGF-like repeats, whereas NECD consists of a series of EGF repeats and a Negative Regulatory Region (NRR). Remarkably, Notch signaling pathway mediates cell to cell communication by transducing short-range signals via interactions between cell-surface receptors (Notch 1-4) with transmembrane ligands [475]. For signaling to occur, the transmembrane ligands from one cell bind the transmembrane Notch receptor in a neighboring cell, inducing the cleavage of Notch and the release of the Notch ICD into the cytoplasm, where it can translocate to the nucleus and promote the expression of its target genes [476]. Notch1-ICD comprises an RBPJ-associated molecule (RAM) domain, seven ankyrin (ANK) repeats, flanked by Nuclear Localization Signals (NLS), a Transactivation Domain (TAD) required for target gene activation, and a C-terminal PEST domain, a region rich in proline (P), glutamic acid (E), serine (S), and threonine (T), which regulates stability and proteasomal degradation of active Notch1- ICD [477,478,479]. While Notch1 contains a strong TAD capable of autonomous transcriptional activation [480,481,482], Notch2 has a weak TAD, while Notch3 and Notch4 have no TAD in the endodomain [483].

The EGF repeats, which are defined by the presence of six conserved cysteine residues forming three disulfide bonds modified with O-glycans at distinct sites, participate in receptor-ligand interactions [484]. The ECD of both Notch receptors and Notch ligands contains numerous EGF-like repeats which are post-translationally modified by a variety of glycans. Inactivation of a subset of genes that encode glycosyltransferases which initiate and elongate these glycans inhibits Notch signaling and cause Notch signaling defects of varying severity [485].

Importantly, strong evidence indicates that deregulation of the components involved in glycosylating Notch proteins are implicated in human developmental disorders and Notch-induced tumorigenesis [486,487,488,489]. Specifically, the EGF repeats of NECD are modified by O-fucose, O-glucose, O-GlcNAc, and O-xylose [490]. To a larger extent, the ligand-dependent Notch signaling pathway requires glycosylation of the NECD for signaling activation [491]. In particular, O-fucose glycans appear to function both directly and indirectly in the recognition of receptors by ligands. For instance, O-fucose glycans directly participate in the binding of Notch1-DLL4 and Notch1-JAG1 [492,493,494]. In 2000, an entirely new field opened up with the discovery that the Fringe molecule is a glycosyltransferase that catalyzes the addition of GlcNAc to O-fucose and this discovery demonstrated an association of the Notch signaling pathway with glycobiology [495,496,497]. Before Fringe can act, EGF repeats must first be glycosylated with an O-fucose and this O-fucosylation is mediated by O-fucosyltransferase 1 (O-FucT-1) (encoded by Pofut1 in mammals), which then are elongated by Fringe, an N-acetylglucosaminyl transferase [498,499]. As fucosylation is one of the prevalent glycosylation types on Notch proteins, O-Fucosylation by POFUT1 is essential for Notch activation in mammals [500,501]. The O-Fucose monosaccharides can then be elongated with GlcNAc residues using Fringe which is essential to promote Notch/Delta-binding, in preference to Notch/ Serrate, whose interaction is inhibited by this modification [502,503]. Similarly, O-glycosylation of the EGF repeats is mediated by O-glucosyltransferase, Rumi in Drosophila or POGLUT1 (also known as hCLP46) in mammals [504, 505,506], and elongated by Shams, a xylosyltransferase. In humans, xylosyltransferase (GXYLT)1 and (GXYLT)2, that add first and second xylose residues to Notch EGF repeats, have been identified [507,508]. The O-glucose modification on Notch is essential for Notch signaling and embryonic development [509,510].

Strikingly, POGLUT1 is overexpressed in primary AML, T-ALL, and other leukemia cell lines [511,512]. In addition, EGF-specific O-GlcNAc-transferase (EOGT in Drosophila and Eogt1 in mammals) adds GlcNAc to EGF repeats. This unique non-nucleocytoplasmic O-GlcNAc modification mediates the ECM interactions of Notch [513,514]. Intriguingly, aberrant Notch activity has either tumor-promoting (oncogenic) or tumor-suppressive roles or both in a context-specific manner [515]. In the hematopoietic system, while an oncogenic role of Notch has been described in several hematologic malignancies including T-ALL, CLL, B-cell leukemias, and lymphomas [516,517,518], a tumor-suppressive role has been proposed in Chronic Myelomonocytic Leukemia (CMML) [519] and also suggested in AML [520]. Such dualism has been linked to the function of Notch in the regulation of cell fate choices during immune cell development [521]. Interestingly, aberrant Notch signaling also triggers anti-apoptotic programs and drug resistance in T-ALL [522], B-ALL [523], CLL [524], AML [525], Hodgkin and Anaplastic Large Cell Lymphoma (ALCL) [526], and MM [527,528]. In this vein, overwhelming evidence indicates that Notch signaling is instrumental in the pathological communication between tumor cells and BM leading to the reprogramming of surrounding microenvironment and the development of pharmacological resistance [529]. Remarkably, the Notch family of receptors and ligands has gained growing interest in recent years due to their early dysregulation in MM and their ability to affect multiple features of the disease, including tumor cell growth, drug resistance, angiogenesis, and bone lesions [530]. For instance, the dysregulation of Notch1 and JAG1 has been associated with progression from a pre-malignant stage termed Monoclonal Gammopathy of Undetermined Significance (MGUS) to MM [531]. Mechanistically, Notch signaling mediates the pathological communications between Bone Marrow Stromal Cells (BMSCs) and MM cells which favors MM progression by increasing MM proliferation [532], promotes chemotherapy resistance, and stimulates angiogenesis [533]. Intriguingly, Notch communication increases osteoclast differentiation and function and induces apoptosis of osteocytes to further promote bone resorption and destruction [534,535]. In addition, Notch signaling also takes part in the migration of MM cells through the expression of the CXCR4/SDF-1 axis system [536]. Unlike other Notch-related malignancies, where the majority of patients carry gain-of-function mutations in Notch pathway members, Notch signaling is aberrantly activated in MM cells due to an increased expression of Notch receptors and ligands [537]. The first outcome of Notch receptors and ligands dysregulation in MM is the activation of Notch signaling within tumor cells due to homotypic interaction among nearby myeloma cells or to the engagement of Notch receptors by ligands expressed on the surrounding BMSCs (heterotypic interaction). The latter contributes to myeloma cell proliferation, survival, and migration, as well as to bone disease and intrinsic and acquired pharmacological resistance [538]. To elucidate further, Notch activation in malignant plasma cells may occur in two distinct ways: MM cells simultaneously express Notch-1, -2, -3 and their ligands (JAG1 and JAG2) resulting in an autonomous pathway activation (homotypic; among MM cells), or Notch activation can be triggered by BMSCs expressing DLL1 or Jagged ligands (heterotypic; between MM cells and host cells). Indeed, in vitro and animal studies show that this dual mechanism of Notch signaling activation increases MM cell proliferation and decreases apoptosis in both human and murine MM cell lines and primary cells from patients [539,540,541,542,543]. In a similar vein, Xu et al., demonstrated that BMSC-derived DLL1 can activate Notch signaling mostly through Notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human MM cells, through the upregulation of CYP1A1 (a member of the cytochrome P450 family involved in drug metabolism). In line with these data, the combined treatment of Notch inhibition with bortezomib resulted in increased bortezomib sensitivity and OS in the 5T33MM mouse model [544]. Within this context, it was shown that DLL1/Notch interaction promotes MM-cell proliferation predominantly in CD138+ MM cells [545]. As a conclusion, the multifunctional role of Notch communication in MM provides a strong rationale to block Notch signaling in the MM tumor niche [546]. In this context, it was shown that Notch inhibition with γ-secretase inhibitors (GSIs) decreases MM tumor growth. Mechanistically, the inhibition of Notch pathway causes decreased MM cell proliferation, induces MM cell apoptosis, and inhibits osteoclastogenesis [547]. In addition, Notch inhibition in MM cells increases their sensitivity to pro-apoptotic compounds such as Bcl-2/Bcl-xL inhibitors. In fact, the pro-survival effect of Notch in MM is due to upregulation of anti-apoptotic proteins like Bcl-2 and Bcl-xL, and downregulation of Bax and Bak, pro-apoptotic proteins [548]. Intriguingly, Notch blockade causes an increase of MM cells sensitivity to standard chemotherapies such as doxorubicin and melphalan both in vitro and in vivo, which ultimately prevents the development of BM-derived drug resistance [549]. Notably, an oncogenic role of Notch has been described in both T-ALL and CLL.

Historically, T-ALL is the hematological neoplasia most closely related to Notch signaling pathway. As a matter of fact, T-ALL is primarily a Notch1-driven disease with somatic gain-of-function mutations in NOTCH1 contributing to almost 60% of the cases [550]. Despite the high prevalence of activating NOTCH1 mutations in T-ALL, NOTCH1 mutations are not associated with unfavorable outcome and in some series they may even confer better prognosis [551,552]. On the contrary, NOTCH1 mutations confer a dismal prognosis with a reduction in the OS in CLL patients. Based on current knowledge, NOTCH1 mutations occur in 11% of CLL patients and are mutually exclusive with tumor protein 53 (TP53) disruptions in 90% of the cases [553]. Intriguingly, their frequency increases in advanced disease phases, as exemplified by the case of RT [554]. Unlike T-ALL, the most common NOTCH1 mutation in CLL affects the C-terminal PEST domain causing prolonged half-life of the cleaved protein [555]. Unsurprisingly, several studies support that NOTCH1 mutations as a negative predictor factor for CLL patients [556,557]. Accumulating evidence suggests that an anti-Notch1 treatment might be able to kill not only mature CLL cells but also their corresponding LSCs, favoring disease eradication for a definitive cure [558]. As mentioned earlier, Notch signaling is an important pathway with both oncogenic and tumor-suppressive potential in AML [559]. Based on current knowledge, NOTCH1 is mutated in 12% of AML patients but its impact on the OS is a debating matter [560,561]. Nevertheless, recent research showed that Notch signaling promotes chemoresistance in FLT3- amplified AML [562]. Intriguingly, Li et al., demonstrated that the combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3-ITD positive AML [563]. In addition, Fischer et al., uncovered the oncogenic relevance of the Notch1 pathway in leukemia with rearrangements of the KMT2A (Lysine methyltransferase 2A) gene (KMT2A-R). By using the Notch1 inhibitor CAD204520, their study demonstrated the successful inhibition of the Notch1 pathway, resulting in convincing anti-leukemic effects, which provides a promising target in the treatment of KMT2A-R AML [564]. Mechanistically, Notch signaling alters the levels of glycosyltransferases that are involved in O-fucosylation and O-glucosylation, which eventually results in a positive feedback loop in AML [565,566,567,568]. Furthermore, Notch2 signaling has been shown to play a key role in marginal zone B-cell development in the spleen, and to be dispensable for the development of other B-cell lineages [569,570]. In this context, NOTCH2 mutations have been found in other B-NHL subtypes, such as splenic marginal zone lymphoma (SMZL) and DLBCL. In DLBCL, NOTCH2 mutations affect approximately 8% of patients with some cases having increased copies of the mutated NOTCH2 allele [571]. In SMZL, NOTCH2 mutations represent the most recurrent genetic lesion accounting for approximately 20–25% of cases [572,573,574]. Unfortunately, Notch-related therapies have not gathered momentum due to the toxicities seen with current therapeutic strategies and the difficulty of targeting multiple Notch ligand-receptor interactions [575]. Hence, there is great hope with the employment of glycobiology in creating novel Notch-related therapies.

Structures common to different glycans

Polysialic acid (PSA)

Polysialic acid is a linear polymer of sialic acid, with α2,8 and α2,9 linkages and a length ranging from 8 to 400 units. In mammalian cells, three sialyltransferases (ST8Sia II, ST8Sia III, and ST8Sia IV) are responsible for the extension of polysialic acid glycans [576]. Polysialylation is an essential glycosylation modification of several important glycoproteins, including the Neural Cell Adhesion Molecules (NCAMs) [577,578], chemokine receptor 7 (CCR7) [579,580], CD36 [581], and E-selectin ligand 1 (ESL- 1) [582]. Because of the large negative charge of PSA, presence of PSA attenuates the adhesive property of NCAM (CD56) and increases cellular motility. In addition, PSA plays important roles in formation and remodeling of the neural system through regulation of the adhesive property of NCAM. In tumor cells, the level of polysialic acid chains correlates with an aggressive phenotype and resistance to cancer treatment [583]. Expression of the polysialated form of NCAM has also been demonstrated in some malignant tumors, such as Wilms’ tumor and small cell lung cancer [584]. The polysialic upregulation in tumors is seen in breast, astrocytoma, and CML [585]. In general, polysialic acid expression correlates with metastatic disease and poor clinical prognosis [586,587,588,589,590].

Type 1 and 2 glycan structures

Type 1 and 2 structures are present on O- and N-glycoproteins as well as on glycolipids. 

A Type-2 unit composed of Galβ1-4GlcNAc, also called N-acetyllactosamine (LacNAc) and a Type-1 unit composed of Galβ1-3GlcNAc. Type 2 structures are ubiquitous, while type 1 structures are found in the GI tract. Types 1 and 2 can both be found in polymers of (Type 1)n and (Type 2)n, with the latter forming polyLacNAc chains, also called i blood group [591].

Poly-LacNAc (poly-N-acetyl-lactosamine) structures

Poly-LacNAcs occur in mammalian glycoproteins in both N- and O-linked glycans. Enzymatically, the action of β-1,6-N-acetylglucosaminyltransferase V enzyme (GnT-5/MGAT5) which catalyzes the addition of ß1,6-N-acetylglucosamine to the α-linked mannose of biantennary N-glycans and core 2 β-1,6- N-acetylglucosaminyltransferase 1 (C2GNT1/GCNT1) which create the ß1,6 branch on Core 2 O-glycans provide added antennae scaffolds for LacNAc formation. Biochemically, both GnT-5/MGAT5 and C2GNT1 enhance the avidity for galectins by promoting poly-N-acetyllactosamine production. N-Glycans generally have longer poly-LacNAc extensions than O-glycans, and both may receive sialic acid or Fuc residues or sulfate. Poly- LacNAcs represent a backbone for additional modifications by fucosyltransferases, sialyltransferases, and sulfotransferases. Poly-LacNAcs have been suggested to be involved in biospecific interactions with selectins and galectins [592]. Poly-LacNAcs are more commonly found on core 2 O-glycans and serve as scaffolds for synthesis of glycan functional groups such as sLeX. Interestingly, the human blood group i and I antigens are determined by linear and branched poly-N-acetyllactosamine structures, respectively. In erythrocytes, the fetal i antigen (linear Poly-LacNAc chain) is converted to the I-blood group antigen (branched Poly-LacNAc chain) by Gcnt2 during development. Dysfunction of the I-branching enzyme may result in the adult i phenotype in erythrocytes [593]. GCNT2 is the gene encoding Gcnt2 responsible for formation of the blood group I antigen. Gcnt2 is an N-acetylglucosaminyltransferase but does not exhibit core 2 activity. Nevertheless, GCNT2 has a critical biological function in modulating EMT and promoting breast cancer metastasis [594].

Lewis antigens

Lewis antigens are synthesized primarily by endodermal epithelia, such as GI epithelia, but are found in endodermal epithelia and RBCs due to transfer of glycolipids to RBCs [595]. Lewis structures are found on type 1 (Galβ1–3GlcNAc-R) and 2 chains (Galβ1–4GlcNAc-R) of O-glycans, N-glycans, and glycolipids. Type 1 chains contain Lewisa/b, while type 2 chains contain Lewis X/Y. The fucosyltransferases are responsible for synthesizing the Lewis antigens [596]. Lewis antigens can also be sialylated and/or sulfated to form sialyl and sulfo Lewis antigens. Sialylation most often occurs at the 3 position of the terminal galactose of the type 1 or 2 chain to form sLeA/X. Sulfo, sialyl, and sulfo sialyl Lewis antigens are important in physiological processes such as inflammation, in particular, because of their role in leukocyte rolling and as selectin ligands. These antigens also play an important role in cancer, which additionally express dimeric Lewis antigens such as sialyl-dimeric Lewis X [597]. LeY antigen is overexpressed by malignant myeloid cells. A second-generation CAR-T anti-LeY evaluated in AML had already demonstrated feasibility and durable in vivo persistence [598]. The increased expression of the sialylated Lewis antigens sLeX and its isomer sLeA has been vastly documented in the majority of cancer types mainly due to the expression of sialyltransferases involved in their intracellular biosynthesis [599]. Noteworthily, sLeA and sLeX are the E-selectin glycan ligands. In particular, overexpression of sLeX is associated with poor prognosis and malignant relapse [600]. Mechanistically, sLeX can promote metastasis by inducing overexpression of E-selectin, resulting in hematogenous metastasis [601]. In fact, by mediating tumor cell attachment to endothelia, platelets, and leukocytes [602,603], sLeA and sLeX enable cancer cells to leave the bloodstream and colonise other organs [604,605,606]. Precisely, attachment to endothelia contributes to vessel invasion, whereas attachment to platelets, and possibly leukocytes, contributes to survival in the vasculature. Interestingly, the leukocyte adhesion deficiency II (LAD II) [also known as Congenital Disorder of Glycosylation IIc (CDG IIc)], in which almost complete deficiency of sLeX expression can be observed, leads to immunodeficiency resulting from interrupting the selectin-mediated leukocyte tethering and rolling on endothelium [607]. In addition, loss of sLeX led to reduced trafficking of lymphocytes to inflamed peritoneum, and reduced lymphocyte homing to lymph nodes [608,609]. Strikingly, the major carriers of selectin ligands are mucins that are heavily O-glycosylated (i.e., the majority of selectin ligands are presented on mucins) [610]. However, the spectrum of selectin ligands on tumor cells is rather broad, encompassing glycolipids, proteins, and glycosaminoglycans [611]. Not surprisingly, the degree of selectin ligand expression by cancer cells is well correlated with metastasis and poor prognosis in cancer patients [612]. E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression, a key endothelial cell factor, also supports BM hematopoiesis via NF-κB-mediated signaling. As an adhesion molecule expressed exclusively by endothelial cells, studies indicate E-selectin as a promoter of the proliferation of HSCs [613]. Experiments involving administration of an E-selectin antagonist or observation of E-selectin knockout mice reported improvement in the dormant state of HSCs as well as potentiation of the self-renewal capacity, strengthening the idea that E-selectin plays a central role in the proliferation of HSCs [614]. In a similar vein, a growing body of literature indicates that binding of E-selectin to sLeX/sLeA on LSCs activates multiple pro-survival signaling pathways and promotes chemoresistance in AML [615,616,617]. Mechanistically, the upregulation of endothelial E-selectin in response to TNF-α released by AML blasts was shown to provide leukemic cells with a pro-survival signal through Akt/NF-κB signaling, conferring chemoresistance [618]. These findings support that constitutive expression of E-selectin in the vascular compartment of BM is a key vascular niche component mediating leukemia survival and chemoresistance via E-selectin ligand/ receptors [619]. Not surprisingly, the expression of E-selectin or its binding epitopes sLeX/sLeA may predict the clinical course and patient outcomes in AML [620,621,622]. Within this context, elevated sLeX/sLeA levels is a hallmark of AML M5 that positively correlated with the expression of transcription factors CEBPA/SPI1. Intriguingly, high expression of sLeX-associated fucosyltransferases FUT3, FUT6, FUT7, and ST3GAL4 have been linked to dismal prognosis in AML in monovariate analyses [623]. Noteworthily, ST3GAL4 is the main sialyltransferase involved in the synthesis of sLeX in myeloid leukocytes [624]. In this vein, transcriptome profiling of multiple genes involved in the synthesis of sLeX from 1074 pediatric patients treated in COG AAML 1031 identified that the increased expression of FUT7 and ST3GAL4 is associated with increased cell surface E-selectin ligand expression and poor prognosis [625]. This renders ST3GAL4/FUT7 as well as their biosynthetic products potentially promising targets for the development of novel glycan-targeting therapies, especially to prevent or overcome the resistance to treatment of high sLeX-expressing AML subtypes such as AML M5 [626]. Not surprisingly, the sLeX/E-selectin axis is an attractive target in AML. One approach employed to target this axis was to exploit the glycomimetic drug uproleselan (GMI- 1271), a carbohydrate analog of sLeX that blocks its interaction with E-selectin, which by disrupting the vascular niche-mediated chemoresistance improved survival of AML patients. In vitro mechanistic studies demonstrated that cytarabine-sensitive AML blasts become chemoresistant upon adherence to E-selectin, but that chemosensitivity can be restored with concomitant incubation with uproleselan. Additional studies showed that the uproleselan-mediated inhibition of E-selectin binding inhibited the activation of NF-κB and Akt and resulted in the attenuation of pro-survival pathways in the leukemic blasts [627]. After showing promising results in a phase I/II study enrolling R/R AML patients (NCT02306291), a phase 3 trial is currently underway to evaluate the efficacy of uproleselan administered with chemotherapy versus chemotherapy alone in patients with R/R AML (NCT03616470) [628,629,630]. In addition, uproleselan may reduce severe and other adverse events associated with AML chemotherapy and HSCT conditioning including mucositis and diarrhea [631]. Furthermore, it was shown that MM cells enriched for E-selectin ligands recognized by the mAb Heca452 (MMHeca452Enriched) were resistant to bortezomib treatment in vivo, and this resistance was reversed by a small glycomimetic molecule, GMI-1271, which inhibits E-selectin/E-selectin ligand interaction [632]. Currently, E-selectin inhibition in MM, by using the specific E-selectin inhibitor GMI1271, is also in clinical trials (NCT02811822).

Glycoconjugates

Glycosphingolipids

Glycosphingolipids are found in the outer leaflet of the plasma membrane of all vertebrate cells and are thought to play functional roles in the regulation of cellular proliferation and differentiation. A number of studies have examined the role of lipid rafts in physical properties and signaling [633]. Glycosphingolipids (GSLs) are a subclass of glycolipids composed of carbohydrates covalently linked to a ceramide (Cer, N-acylsphingosine) lipid tail that anchors the molecule within the cell membrane. Biologically, these ceramide-linked glycans are major components of the outer cell plasma membrane that play essential roles in cell signaling, apoptosis, adhesion, receptor modulation, growth and differentiation [634,635,636]. Cellular differentiation and malignant transformation are often accompanied by dramatic changes in GSL expression. Many GSLs are capable of inducing differentiation, apoptosis, BM suppression and metastasis [637,638,639]. Abnormal GSL expression is associated with the development of many types of cancers including leukemia [640]. GSLs are usually divided into two major families, known as galactosylated (galactocerebroside; GalCer) or glucosylated ceramides (glucocerebroside; GlcCer). Further extension and modifications of these core structures, including elongation, sulfation, and sialic acid acetylation, contributes to the diversity of the repertoire expressed in (immune) cells. Glucosylceramiderelated GSLs are further divided into three major classes based on the action of specific glycosyltransferases; (iso)globo- (A4GALT), ganglio- (B4GALNT1 and ST3GAL5), and (neo-) lacto (B3GNT5) –series [641]. The (iso)globosides globotriaosylceramide (Gb3) and isoglobotriaosylceramide (isoGb3) are generated by the addition of a galactose to lactosylceramide (LacCer) (also known as CD17/ CDw17) in α1,4 and α1,3 linkages by α1,4-galactosyltransferase (A4GALT) and α1,3-galactosyltransferase 2 (A3GALT2) respectively. The B3GNT5 gene encodes the glycosyltransferase β1,3-N-acetylglucosaminyltransferase (β3Gn-T5), a lactotriaosylceramide (Lc3Cer) synthase, which is a key enzyme for the biosynthesis of (neo)lacto-series GSLs (Lc3 and nLc4) [642]. Lc3Cer is a precursor structure for lacto-/neolacto-series glycolipid and polylactosamine chains elongated on Lc3Cer. β3Gn-T5 exhibits the strongest activity to transfer GlcNAc to glycolipid substrates, such as LacCer and neolactotetraosylceramide (nLc4Cer; paragloboside), resulting in the synthesis of Lc3Cer and neolactopentaosylceramide (nLc5Cer) respectively [643]. β3Gn-T5, together with its associated glycosidic product (Lc3), plays critical roles in embryonic development and differentiation. Its expression in leukemia cell lines has been reported previously [644]. It has also been suggested as a differentiation-associated GSL in the BM of AML patients with corresponding elevated B3GNT5 expression [645]. Previous studies have indicated that certain GSLs play a critical role in the differentiation of AML cells. Within this context, the best described myeloid-specific GSL is nLc4 (a fucosylated neolacto-series GSL which is known as the CD65 antigen) [646,647,648]. CD65 is expressed on most myeloid cells during development, highly on granulocytes and weakly on monocytes in Peripheral Blood (PB). The sialylated form of CD65 (CD65s) is expressed when the myeloid progenitor antigen CD34 disappears, indicating that CD65s expression marks a turning point in myeloid cell differentiation [649].

Gangliosides

GSLs are further subclassified as neutral (no charged sugars or ionic groups), sialylated (having one or more sialic acid residues), or sulfated. Traditionally, all sialylated GSLs are known as “gangliosides” regardless of whether they are based on the ganglio-series neutral sugar core [650]. Gangliosides participate in the regulation of various cellular functions, including cell proliferation, apoptosis, migration, and invasion. Moreover, they have been shown to regulate RTK signaling [651]; and their expression changes during malignant transformation, both at the quantitative and qualitative levels [652]. Gangliosides are a family of glucosylceramide-related GSLs characterized by an α2-3 linked sialic acid that is added onto the core GSL structure lactosylceramide (LacCer) by the sialyltransferase ST3GAL5 [653]. The product of ST3GAL5 action, known as GM3, serves as a precursor for most of the more complex ganglioside species (GM3 is the parent structure for a-, b-, and c-series gangliosides). Moreover, β1,4-N-acetylgalactosaminyltransferase (GM2/GD2 synthase) is a key enzyme which catalyzes the conversion of GM3, GD3 (disialolactosylceramide) and lactosylceramide (LacCer) to GM2, GD2 and asialo-GM2 (GA2), respectively. This step is critical for the synthesis of all complex gangliosides enriched in the nervous system of vertebrates [654]. Overwhelming evidence indicate that AML cells have high expression of GM3 which was found to induce monocytic differentiation in leukemia cells [655]. In a recent study by Wang et al., GSLs with Neu5Gc were found in most AML cell lines, including GM3 (Neu5Gc), GD3 (Neu5Gc), GM1a (Neu5Gc), and two glycans in the (neo)lactoseries. However, the abundance of glycans with Neu5Gc varied between cell lines. The cell lines of the M6 subtype showed a high expression of gangliosides with α2,3-sialylation and Neu5Gc, as compared to the M2 and M5 subtypes which were characterized by high expression of (neo)lacto-series glycans and Lewis A/X antigens (an average Neu5Gc expression of 2.3% in M6 cell lines vs. only 0.8% in the rest of the AML cell lines). The authors conclude that glycans with Neu5Gc could be potential therapeutic targets for M6-stage AML [656]. In a similar vein, the GSL and gangliosides expression profiles were analyzed in the BM samples of AML patients in previous important study (Table-3). Interestingly, AML patients had 16-fold higher expression of the Lc3 synthase β3Gn-T5 than healthy subjects (P < 0.05). The authors suggested the exploitation of Lc3 as a potential biomarker and a target for therapy since it is highly expressed in primary AML cell lines [657]. Furthermore, GD3 is increased in lymphoblasts with a T-cell immunophenotype compared to non-T-ALL blasts. Consequently, GD3 expression was observed in T-ALL [658,659], and ATLL cells [660]. Despite that the differential expression of GM2 and GD2 in malignant cells is regulated by the enzyme activity of GM2/GD2 synthase, the amount of precursor structure present in individual cell lines is also a very important factor in determining the ganglioside profile [661]. Within this context, ATLL cell lines specifically express GD2 but not GM2 [662]. On the other hand, GM2 is an ideal target for anti-cancer therapy since normal cells express little GM2. Interestingly, DMF10.167.4, a hamster anti-GM2 mAb raised against a murine T-cell lymphoma cell line, has been shown to induce apoptosis in vitro [663].

Note: ¹The significantly higher expression of Lc3 in the M1 subtype than other subtypes indicates that the expression of Lc3 is closely related to cell differentiation in human bone marrow.
²Acute myeloblastic leukemia with granulocytic maturation.
³Gb3 did not differ significantly between the control and AML groups, whereas Lc3, GM3 and nLc4 had significantly higher expression in the bone marrow samples of AML patients.
FAB, French–American–British; Gb3, globotrihexosylceramide; GM3, monosialodihexosylganglioside; GSL, glycosphingolipid; Lc3, lactotriaosylceramide; Lc4, lactotetraosylceramide; nLc4, neolactotetraosylceramide

Table 3: Expression GSLs and gangliosides according to the AML FAB subtypes

O-acetylation

O-acetylation of the sialic acid residues is one of the most common modifications of gangliosides [664]. O-acetylated ganglioside species represent therapeutic targets of interest as an alternative strategy to non-O-acetylated ganglioside species. For example, targeting OAcGD2 rather than GD2 seems to be a better strategy due to exclusive OAcGD2 expression in cancer tissue [665]. In a similar vein, targeting 9-O-Ac-GD2 ganglioside, a modified GD2 ganglioside which is expressed in neuroblastoma, SCLC, melanoma, renal carcinoma and lymphoma [666], circumvents the significant neuropathic pain secondary to complement activation on anti-GD2 bound peripheral nerves [667], that limited the therapeutic application of anti-GD2 mAbs [668]. In particular, the 9-O-acetylation of gangliosides has been extensively associated with cancer, and hence considered as a marker of cell and tissue growth. The most prominent one is 9-O-Ac-GD3 (also called CD60b), which is considered as an oncofetal marker in animal and human tumors like neuronal tumors, melanoma, basalioma or breast cancer, as well as in psoriatic lesions [669]. Similar to melanoma and glioblastoma, O-acetyl-GD3 seems to contribute to drug resistance capacity in ALL cells [670]. As a matter of fact, the survival and drug resistance of lymphoblasts critically depend on 9-O-acetylation, which was found on both GD3 and sialoglycoproteins [671,672]. Specifically, pre-B ALL cells surviving chemotherapy have increased cell surface 9-O-Ac- GD3 and 9-O-acetylated α2,3 or α2,6-linked sialoglycoproteins as reported by CCA lectin. Later, Joo et al., identified nucleolin (NCL), a multifunctional nucleolar protein, as a sialoglycoprotein modified by 9-O-acetylation in pre-B ALL, and proposed it as a possible therapeutic target [673]. Interestingly, recent clinical and experimental evidence suggested that overexpression of NCL is linked to drug resistance in B-ALL [674].

Glycosaminoglycans and proteoglycans

Rather than existing in glycoconjugates, glycans can also be secreted without conjugation to other macromolecules in the form of glycosaminoglycans (GAGs). GAGs are a family of highly sulfated, complex, unbranched (linear), often long, polysaccharides with a repeating disaccharide unit. GAG chains, the essential functional parts, are often highly sulfated, with resulting capability to bind cytokines, chemokines, or growth factors. As such, GAGs are extremely important biomolecules of the ECM, as they modulate protein function and stability. GAGs can tether ligands to RTKs, resulting in constitutive activation independent of protein/RNA levels. 

GAGs regulate a variety of cellular interactions in the BM because they are expressed by both the BM stroma and by normal hematopoietic cells [675,676]. In industry, incorporating GAGs into biomaterials has emerged as a widely adopted strategy in medical applications, owing to their biocompatibility and ability to control the release of bioactive molecules [677]. Based on the difference of repeating disaccharide units, GAGs can be categorized into four main groups: Heparin/Heparan Sulfate (HS), Chondroitin Sulfate (CS)/Dermatan Sulfate (DS), Keratan Sulfate (KS), and hyaluronan (also known as hyaluronic acid, HA). GAGs can be covalently connected to a core protein forming Proteoglycans (PGs) or secreted, like hyaluronic acid (HA). HA does not form covalent links with proteins but instead interacts noncovalently with proteoglycans via hyaluronan-binding motifs [678,679]. HA and HS are two typical GAGs found in the ECM and on the cell surface with the basic repeating disaccharide unit composed of a uronic acid residue and a glucosamine residue [680]. CD44, a type I transmembrane protein and member of the cartilage link protein family, is the principal cell surface receptor for HA [681]. Interestingly, the discovery of CD44 as a receptor for HA made possible to understand why one of the HA physiological functions was to capture circulating cells such as lymphocytes and lead them to inflamed sites. The interactions between HA and CD44 leads to cell survival, cell growth, invasion, and metastasis via signaling networks including RhoGTPases, PI3K/AKT pathway, and other chemoresistance pathways via ROK activation [682]. Intriguingly, heparin, the most acidic macromolecule of human body acting as an anticoagulant, is a highly sulphated variant of HS [683]. Despite that heparin and heparan sulphate differ significantly with regard to their chemical composition [684], heparin is often considered an analogue of heparan sulphate that commonly substitutes it in experimental models studying HS [685]. HS is produced by virtually all cells in the body; in contrast, heparin is confined to connective-tissue-type mast cells [686]. Moreover, HS regulates a wide array of functions during both developmental and physiological processes, including cell adhesion, migration, proliferation and differentiation, cellular signaling, ECM assembly, and also during numerous pathological disorders, such as cancer or infectious and neurodegenerative diseases [687]. On the other hand, KS is involved in a range of biological processes such as cornea transparency, embryonic development, wound healing, cell adhesion, and migration; and dysregulation of its biosynthesis has been associated with a poor prognosis of various cancers [688]. Ubiquitous on cell surfaces and within the ECM in higher eukaryotes, proteoglycans are large biomolecules that consist of a protein part, the so-called core protein, which is glycosylated with sulfated and thereby negatively charged GAGs. By participating in the organization of ECM and regulating its mechanical properties, proteoglycans provide structural support in connective tissues such as cartilage. In addition, proteoglycans are well established as key players in supporting the dynamic ECM. In this regard, proteoglycans interact with growth factors, cytokines, and chemokines protecting them from degradation and form effective gradients of these components in ECM [689]. Mechanistically, proteoglycans act as co-receptors for these molecules promoting their signaling. In fact, the vast majority of signaling events between cells or with the ECM are modulated by the associated GAG chains [690]. For instance, growth factors, neurotrophic factors and chemokines can be recruited to target cells through GAG binding sites, rendering proteoglycans important determinants for development [691,692]. Furthermore, proteoglycans regulate cell behavior and phenotype, and are involved in cell proliferation, adhesion, migration and invasion [693]. It is worth noting that changes in proteoglycans and GAGs modulate virtually all the hallmarks of cancer, highlighting their relevance to malignant disease [694]. A textbook example is the role of cell surface heparan sulfate proteoglycans (HSPGs) in sustaining proliferative signaling, the first hallmark of cancer [695]. Not surprisingly, HSPGs have emerged as key molecules in tumor progression and communication [696]. HSPGs are ubiquitously found at the cell surface and ECM in all the animal species. In addition, HSPGs are key regulators of the BM niche of normal hematopoietic stem cells [697]. It is worth noting that HSPGs can be roughly divided into three groups according to their location: cell surface or membrane HSPGs, such as syndecans and glycosylphosphatidylinositol-anchored proteoglycans (glypicans), the secreted ECM HSPGs (agrin, perlecan, type XVIII collagen), and the secretory vesicle proteoglycan, serglycin [698]. Noteworthily, perlecan is the main HSPG in the blood vessels ECM. Cell surface HSPGs may also be secreted into the matrix because of enzymatic cleavage of core proteins. Other cell surface HSPGs include CD44 and beta glycan [699]. Intriguingly, tumor-specific HSPGs differ in composition from HSPGs in corresponding normal tissue which suggests that agents that bind HS or modify its synthesis could lead to selective targeting of tumor cells and tumor microvasculature [700]. In this vein, HSPGs play important roles in cancer initiation and progression, by interacting with the signaling pathways that affect proliferation, adhesion, invasion and angiogenesis. Not surprisingly, overexpression of HSPGs is associated with increased tumorigenesis, angiogenesis and invasiveness in several cancers including MM, breast, and pancreatic cancer [701,702]. Mechanistically, cell surface HSPGs act as coreceptors for growth factor-mediated RTK signaling, where the HS chain aids in the formation of a ternary complex of growth factor, receptor tyrosine kinase, and the GAG chain, which substantially promotes and enhances mitogenic signaling promoting tumor growth [703]. Interestingly, growth factor binding to HS is driven by heparan sulfation, the addition of negatively charged sulfate groups to the HS chain. Misexpression of the enzymes that catalyze heparan sulfation is associated with invasion, metastasis, and angiogenesis in solid tumors. Nevertheless, pediatric AML patient cohort analyses demonstrated that increased 6-O-heparan sulfotransferase 1 (HS6ST1) expression is associated with worse patient survival, suggesting that HS6ST1 influences AML chemosensitivity. It is worth noting that HS6ST1 is responsible for 6-O-sulfation of heparan sulfate (a specific form of heparan sulfation). Within this context, Termini lab used CRISPR/Cas-9 editing to knockout HS6ST1 from MOLM-13 AML cells to show that HS6ST1-knockout cells had a significantly increased percentage of necrotic cells than Control cells upon cytarabine (Ara-C) treatment. Bulk RNA sequencing revealed that IL2-STAT5 signaling is significantly downregulated in HS6ST1-knockout cells than Control cells. These results indicated that 6-O sulfation inhibits Ara-C-mediated cell death via STAT5 [704]. In a similar vein, many anti-cancer drugs alter HSPGs expression, have an anti-tumor effect and decrease or inhibit the activity of HSPGs or enzymes responsible for their regulation, which suggests HSPGs as a promising anticancer drug targets for the treatment of several cancers including hematologic malignancies [705].

Serglycin is emerging as the dominant proteoglycan species expressed by immune cells that play crucial roles in diverse immunological processes. Despite being originally regarded as a hematopoietic cell proteoglycan, serglycin is expressed by several nonhematopoietic cell types. A unique property of serglycin is its ability to change its structural and functional characteristics, likely because of its remarkably variable glycosylation pattern in different serglycin-expressing cell types [706]. Notably, heparin is the most well-known serglycin-associated GAG and heparin PG serglycin occurs in the granules of connective-tissue-type mast cells. However, serglycin may also contain CS chains. Whereas the connective-tissue-type mast cells predominantly synthesize GAG chains of heparin type, the mucosal-type mast cells synthesize mainly CS chains [707]. Interestingly, serglycin bearing CS chains occur in most blood cells. Strikingly, serglycin exclusively carrying CS side chains is constitutively secreted by MM cells. Noteworthily, serglycin is the major proteoglycan secreted by MM cells, but is also present on the cell surface of myeloma plasma cells and affects bone mineralization [708,709]. Moreover, serglycin can be a useful marker in the diagnosis of AML where it was more specific than Myeloperoxidase (MPO) in distinguishing AML from Philadelphia chromosome-negative chronic myeloproliferative disorders [710]. Furthermore, syndecans and glypicans are the two major families of cell-surface HSPGs. Syndecans (SDCs) are a family of four transmembrane HSPGs that act in cooperation with key transmembrane receptors and ECM molecules mediating pleiotropic functions, such as signaling, adhesion, proliferation, migration, apoptosis, and differentiation [711]. In terms of structure and sequence, syndecan-1 (CD138) and syndecan-3 can be considered one subfamily and syndecan-2 (CD362) and syndecan-4 another. Although all syndecans bear HS glycan chains, only syndecan-1 and syndecan-3 can also bear CS glycan chains [712]. Syndecan-1 is highly expressed in MM cells [713]. In fact, syndecan-1 is the dominant HSPG expressed on the surface of myeloma cells and is used as a standard marker by many laboratories for identification and purification of these tumor cells [714,715,716,717]. In addition, cell surface syndecan-1 is shed from myeloma cells and is present at high levels in the serum of some myeloma patients [718]. Due to the high levels of syndecan-1 on the surface of myeloma cells and the abundance of shed syndecan-1 that accumulates within the TME, myeloma cells in the BM are literally bathed in biologically active HS [719]. Seidel et al., demonstrated that high levels (approximately five times the level of normal controls) of syndecan-1 in the serum of MM patients are an independent predictor of poor prognosis [720]. Strikingly, high-serum syndecan-1 enhances both the growth and metastasis of myeloma tumors [721,722]. Syndecan-1 exerts its growth-promoting effects by regulating the activity of many effector molecules important for myeloma growth and survival, including Hepatocyte Growth Factor (HGF), a growth factor known to be up-regulated in many myeloma tumors [723], that binds to the heparan sulfate of syndecan-1 and helps potentiate signaling via the cMET receptor with resulting cell proliferation [724].

Furthermore, Spinler et al., identified syndecan-1 as an important marker for aggressive CML cell populations, indicating that syndecan-1 may be a viable biomarker for disease risk or a potential clinical target to control CML [725].

Heparanase (HPSE)

Heparanase is the only mammalian endoglycosidase that cleaves heparan sulphate releasing biologically active fragments of heparan sulfate. Acting together, heparanase and heparan sulfate facilitate tumor cell arrest, extravasation, and metastasis. Heparanase is upregulated in essentially all human tumors in which the severity of tumor metastasis is directly proportional to heparanase levels [726]. Mechanistically, the enzyme promotes metastasis by degrading HSPGs in basement membranes, facilitating passage of tumor cells through the vascular wall [727]. As the enzyme releases HS-bound angiogenic factors from the ECM, heparanase upregulation also correlates with increased tumor vascularity and poor postoperative survival of patients with cancer [728]. Not surprisingly, heparanase is considered a master regulator of the aggressive cancer phenotype [729,730,731,732]. Noteworthily, heparanase is upregulated in response to chemotherapy which promotes chemoresistance coupled with poor prognosis. Mechanistically, the surviving cells with heparanase upregulation acquire chemoresistance, at least in part, due to autophagy. Consequently, heparanase inhibitors used in tandem with chemotherapeutic drugs overcome initial chemoresistance, providing a strong rationale for applying anti-heparanase therapy in combination with conventional anti-cancer drugs [733,734]. In fact, several studies have shown that heparanase inhibition by heparin derivatives attenuates tumor growth and metastasis [735,736,737,738,739]. Intriguingly, heparanase activity has been strongly implicated in the progression of MM [740,741]. Mechanistically, heparanase synergizes with syndecan-1 in promoting myeloma progression [742]. Heparanase also enhances myeloma progression via CXCL10 down-regulation, suggesting that this chemokine exerts tumor-suppressor properties in myeloma [743]. In a similar vein, heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells [744]. Further, heparanase promotes myeloma stemness and in vivo tumorigenesis [745]. Strikingly, AML-heparanase promotes the spontaneous metastasis of myeloma cells to the bone [746]. Heparanase is present in the BM of most MM patients where high levels of heparanase enzyme activity correlates with elevated angiogenic activity, an important promoter of myeloma growth and progression [747]. Ramani et al., discovered that gene expression profiling of tumor cells from myeloma patients revealed that heparanase expression was high in the cells that survived and grew following chemotherapy. Strikingly, tumor cells that survive intensive chemotherapy in myeloma patients express high heparanase. They also found that heparanase enhances myeloma drug resistance while blocking heparanase-driven ERK signaling sensitizes myeloma cells to chemotherapy [748]. Mechanistically, frontline anti-myeloma drugs, bortezomib and carfilzomib activate the NF-κB pathway to trigger heparanase expression in tumor cells. Activated NF- κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines. In addition to enhancing heparanase expression, chemotherapy also caused release of heparanase by tumor cells into the conditioned medium. This soluble heparanase was taken up by macrophages and triggered an increase in TNF-α production. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP- 9 and activated ERK and Akt signaling pathways. These changes induced by heparanase are known to be associated with the promotion of an aggressive tumor phenotype [749]. On the other hand, heparin-derived compounds with heparanase inhibitory activity have been shown to effectively attenuate myeloma tumor growth and bone metastasis [750,751]. Interestingly, the development of these compounds began by observing heparin capacity to inhibit HPSE activity because of its competition with HS for binding to the enzyme [752]. In this context, targeting heparanase activity using Roneparstat (SST0001), a chemically modified non-anticoagulant heparin (that is devoid of any significant anticoagulant activity) with potent anti-heparanase activity, blocks the multiple pathways that are stimulated by heparanase (e.g., syndecan shedding, angiogenesis) resulting in decreased drug resistance and inhibition of myeloma growth in vivo [753]. Analysis of myeloma tumors from animals treated with Roneparstat demonstrated that these tumors have diminished levels of VEGF, HGF and MMP-9, reduced angiogenesis and reduced levels of shed syndecan-1 compared to animals treated with vehicle. This highlights that the mechanism of action of Roneparstat is consistent with it having anti-heparanase activity in vivo [754]. However, heparanase inhibition is not expected to cause direct MM cell killing as demonstrated in phase I, first-inhuman trial designed to assess the safety and tolerability profile of Roneparstat in patients with R/R MM (NCT01764880) [755]. Instead, exploration of roneparstat in combination regimens for the treatment of MM should be the next step in this field. In this vein, Ramani et al., demonstrated the synergistic effect of Roneparstat when associated with bortezomib or melphalan. By using an in vivo model of disseminated myeloma, where MM cells expressing a high level of heparanase home and grow exclusively in bone, Roneparstat in combination with either bortezomib or melphalan, significantly decreased both the number of animals with detectable tumors and tumor burden compared to animals treated with either of these drugs alone. Weissmann et al., found that heparanase is expressed by human follicular and diffused non-Hodgkin's B-lymphomas, and heparanase inhibitors restrain the growth of tumor xenografts produced by lymphoma cell lines [756]. It is worth noting that pixatimod (PG545) is another potent inhibitor of heparanase [757] as well as a novel clinical-stage immunomodulatory agent, which was found to stimulate innate immune responses against tumors in preclinical cancer models. Pixatimod is capable of inhibiting the infiltration of TAMs via the inhibition of heparanase yet it also activates NK cells through toll-like receptor 9 (TLR9)-dependent stimulation of DCs [758]. Pixatimod is a cholestanol-sulfo-tetrasaccharide conjugated small molecule compound. The oligosaccharide backbone of pixatimod is derived from starch, and retains the amylose structure of α(1 → 4)-linked glucose residues. Coupling the sulfated oligosaccharide to a lipophilic cholestanol aglycone significantly increased the elimination half-life in vivo, while reducing the unwanted anticoagulant activity associated with similar compounds but retaining the potent inhibition of heparanase [759]. Due to lack of objective responses using pixatimod as a monotherapy [760], pixatimod has been tested in combination with a number of approved anti-cancer drugs demonstrating its clinical potential, including with gemcitabine, paclitaxel, sorafenib, platinum agents and an anti-PD-1 antibody [761]. Brennan et al., found that pixatimod had potent antitumor activity in murine models of B-cell and T-cell lymphomas. Investigation into the mechanism revealed that the in vivo antitumor effect of pixatimod was critically dependent on NK cell activation and that NK cell activation by pixatimod was mediated through myeloid differentiation primary response 88 (MyD88)- dependent TLR9 pathway in vivo, thus suggesting the significance of capitalizing on pixatimod as a novel and effective NK-activating agent for the treatment of lymphomas [762].

The cell surface proteoglycan CD44 (H-CAM)

The most studied form of Tn antigen is found in mucins (particularly MUC1). However, Tn antigen is also expressed on the adhesion molecule CD44 that mediate the response of cells to their cellular microenvironment [763]. Activation of CD44, a cell surface adhesion receptor (referred to as the lymphocyte homing-associated cell adhesion molecule, H-CAM) that is highly expressed in many cancers [764], is initiated by binding to its ligand HA [765]. In addition, the hyaluronate receptor CD44 also binds to other components of ECM including other GAGs, serglycin, fibronectin, collagen type I and type IV, laminin, and osteopontin (OPN). In this way, CD44 functions as an adhesion molecule for cell-cell and cell-ECM interactions [766]. In particular, serglycin serve as a novel ligand for CD44 to regulate lymphoid cell adherence and activation [767]. Guo et al., showed that serglycin is frequently overexpressed in lung adenocarcinomas, and functions in promoting NSCLC cell migration, invasion and stemness in a CD44-dependent manner [768]. In addition to tethering cells to extracellular ligands as cell-adhesion molecule, CD44 also participate in cellular signaling cascades through association with the actin cytoskeleton [769]. Interestingly, CD44 is a heavily glycosylated protein (class I transmembrane glycoprotein). N-glycosylation and sialylation regulate CD44 binding to HA; CD44 O-glycosylation regulates the tumor aggressiveness, and fucosyltransferase-mediated CD44 fucosylation promotes tumor progression [770,771]. Hematopoietic cell E/L-selectin ligand (HCELL) is a specific glycated form of sialofucosylated CD44 that is characteristically expressed on human hematopoietic stem cells and is the most potent E-selectin and L-selectin expressed on human cell prime ligands [772]. HCELLs have been shown to be present at high levels in human malignant hematopoietic cells, including neonatal Acute Myeloid Leukemia (AML) cells and the AML derived primitive human hematopoietic progenitor cell line KG1a [773,774]. Strikingly, aberrant expression and dysregulation of CD44 enhance tumor initiation and progression [775]. CD44 can directly potentiate RTK signaling pathways and act as a coreceptor for several growth factors, such as Met, VEGFR-2 and EGFR, thus enhancing cancer cell proliferation and correlating with poor prognosis and metastatic potential [776]. Moreover, HA-CD44 interactions induce highly malignant, chemotherapyresistant cancer stem-like cells [777]. Mechanistically, HA-CD44 interactions promote cancer cell migration through SRC-induced cortactin cytoskeleton function [778]. CD44 is overexpressed in many cancers of hematopoietic and epithelial origins [779]; where its expression is correlated with the tumor biological behaviour including tumorigenesis, growth, metastasis and prognosis [780]. As CD44 contributes to the cancer stem/initiating phenotype, CD44 was identified as stem cell marker of HSCs [781], as well as a universal CSC marker in many cancers [782,783]. Not surprisingly, cells overexpressing CD44 possess several CSC traits, such as self-renewal and Epithelial-Mesenchymal Transition (EMT) capability, as well as a resistance to chemo- and radiotherapy [784]. The importance of adhesive interaction between CD44 and HA (which is a component of the BM ECM) to maintain Leukemia-Initiating Cells (LICs) in the BM niche has been confirmed using an anti-CD44 antibody, soluble HA, or hyaluronidase [785,786]. In AML, the CD44 cell surface antigen is expressed on leukemic blasts in all subtypes. As a CD44 is a key regulator of AML LSC function, targeting of CD44 eradicates human acute myeloid leukemic stem cells [787]. In a similar vein, CD44 is also involved in the arrest of myeloid differentiation; Charrad et al., demonstrated that CD44 ligation (by HA as well as CD44 antibodies) can reverse the differentiation blockage in AML M1/2 to AML M5 subtypes, and in this scenario CD44- targeted differentiation was comparable to that obtained in AML M3 with retinoic acid [788]. In ALL, high CD44 expression is seen in high risk T-ALL while CD44 expression was significantly lower in the TEL/AML1 (ETV6-RUNX1) ALL subtype (expressed from the t(12;21) translocation) that defines a subgroup of patients with an excellent prognosis [789]. In addition, CD44 signaling plays a pivotal role in regulating the proliferation of CML cells by modulating the expression and activity of the Wnt/ β-catenin signaling pathway [790]. The full-length CD44 gene consists of 20 exons in mice but 19 exons in humans (exon 6 is missing in humans). Exons 6–14 of the CD44 gene in humans (known as variant or variable exons, CD44v2-v10) undergo extensive Alternative Splicing (AS) via excision or inclusion in various combinations in the membrane-proximal stem region to generate splicing variants (CD44v isoforms) [791]. The smallest and the most expressed CD44 isoform is the CD44 standard (CD44s), constructed of ten constant exons with no variant exons [792]. CD44s, referred to as hematopoietic CD44 (CD44H), is expressed mainly on cells of lymphohematopoietic origin [793]; while, CD44v are predominantly expressed on epithelial cells [794], including epithelial-type carcinomas, particularly those in advanced stages [795]. Furthermore, serum soluble CD44 (sCD44) levels can be used as circulating tumor markers. Elevated levels of sCD44s and sCD44v6 were associated with an advanced disease in B-CLL [796]. Patients with higher than median sCD44 levels had a more advanced clinical disease stage, and had a median Progression-Free Survival (PFS) of 36 months, whereas patients with an sCD44 level < 642 ng/ml experienced a longer PFS of the average of 8 years. This indicated that serum sCD44 levels may represent a reliable prognostic marker that might be used for predicting the risk of disease progression in patients with early B-CLL [797]. Elevated levels of serum soluble CD44 (sCD44) were also reported in adult lymphomas and leukemias with a poorer treatment outcome [798,799]. Similarly, Tacyildiz et al., found that serum sCD44 levels were significantly high in pediatric patients with Hodgkin lymphoma (HL) and NHL who were in advanced stages of disease in contrast to significantly low levels in patients who were in complete remission (CR) [800]. Despite that CD44 blockade can lead to the elimination of leukemia initiating cells, anti-panCD44 can interfere with hematopoiesis. Hence, CD44v-specific targeting is a better option that targeting CD44 itself [801]. The extra domain formed by variant exons after distinct AS and assembly is able to interact with and sequester different growth factors, as well as cytokines, thus endowing CD44 with additional functions [802]. Mechanistically, CD44v displays a greater affinity to HA compared to CD44s [803].

In this context, compelling evidence indicates that major HA-CD44 signaling pathways involve a specific variant of CD44 isoforms. For example, HA/CD44v6 interaction can drive tumor metastasis by activating RTKs signaling pathways [804,805]. Consequently, CD44v expression is directly proportional to increased metastatic spread in several hematologic and solid malignancies and poor prognosis [806]. At instance, CD44v surface levels in CLL can identify a subgroup of patients with significantly worse prognostic features [807]. Within this context, targeting and inhibiting CD44 through neutralizing antibodies was shown to be cytotoxic in CLL cells, particularly in patients with CLL that express ZAP-70, but had little effect on normal B-cells [808]. Among the various CD44 isoforms, the v6 exon-containing isoforms (CD44v6) is implicated in tumorigenesis, tumor cell invasion and metastasis [809]. In fact, CD44v6 is currently the most established tumor antigen among the CD44 splice variants [810]. CD44v6 is found to confer metastatic potential to non-metastatic tumor cells [811]. CD44v6 is relatively tumor-restricted and associated with poor prognosis in AML [812,813], and MM [814]. Interestingly, Casucci et al., showed that CD44v6 is required for AML and MM cell growth in vivo and appealing target to select in order to avoid immune evasion as a result of antigen-loss variants. In in vivo models of AML and MM, CD44v6 CAR T-cells were found to provide significant anti-tumor activity without affecting either CD44v6- expressing keratinocytes or hematopoietic stem cells [815,816]. CD44v6 facilitates homing of MM cells to the BM and their adhesion to BM stroma is dependent on CD44v6 expression which is upregulated by contact of the MM cells to BM endothelial cells [817]. Furthermore, CD44v6 expression was observed predominantly in aggressive NHLs (aNHLs) where it display strong prognostic potential and identify patients with an unfavourable outcome [818,819,820]. For example, CD44v6 is particularly important for predicting worse prognosis in DLBCL [821]. Likewise, surface CD44v6 expression was significantly correlated to poorer OS in B-CLL [822] and ALL [823,824]. In addition to the Tn antigen, CD44v6 can also carry TF [825], sTn [826], and sLeA antigens [827]; where it correlates with the metastatic potential of several cancers. Intriguingly, overexpression of CD44v9 is related to an unfavorable clinical presentation in MM and high-grade NHL [828]. In MM, acquired CD44v9 expression can occur during disease progression [829]. The CD44v10 isoform displays prognostic relevance by being correlated to initial BM involvement and risk of relapse in Nodular Sclerosing HL (NSHL) [830]. In CML, Holm et al., showed that CD44v3 (containing variant exons 8–10) is elevated during CML progression from chronic phase to blast crisis. Furthermore, although CD44 mAb and dasatinib treatment significantly reduced blast crisis chronic myeloid leukemia stem cells (BC LSCs) self-renewal in the splenic niche and lowers self-renewal in BM, some BCR-ABL1– and CD44v3-expressing cells persist in the BM niche following combination therapy, suggesting that a CD44v3-specific mAb may be more effective at eradicating BC LSCs from the more recalcitrant BM niche in CML [831].

The B cell receptor and immunoglobulins

The B-cell Receptor (BCR) and its secreted counterpart, Immunoglobulins (Igs) (also called antibodies (Abs)) are two important glycoproteins involved in B-cell biology. It has been indicated that glycans expressed by these B-cell-specific molecules can modulate immune activation via glycan-binding proteins [832]. Compelling evidence indicates that the BCR pathway is activated in CLL, DLBCL, Burkitt Lymphoma (BL), Follicular Lymphoma (FL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL), and Waldenstrom’s Macroglobulinemia (WM), which represent a potential therapeutic target [833]. Unfortunately, BCR-targeting drugs often fail to produce durable responses despite their initial effectiveness [834]. It has been repeatedly demonstrated that the development and function of B-cells depend on signals from the BCR. Indeed, healthy B-cells depend on surface BCR for survival and metabolic fitness. There are two principal types of BCR signaling: antigen-dependent and antigen-independent or “tonic” BCR signaling. Tonic BCR signaling is a constitutive signaling that mainly relies on the PI3K/AKT pathway and is crucial for B-cell survival. By contrast, antigen-dependent BCR signaling relies on the NF-κB pathway and plays an important role in humoral responses inducing B-cell proliferation, cytidine deaminase (AID) expression, affinity maturation and differentiation [835]. Similar to normal B lymphocytes, B-cell lymphomas including CLL and other NHLs also depend on the presence of an intact BCR signal transduction pathway encompassing both types of BCR signaling [836]. Structurally, the BCR is made of surface-bound Ig (either IgA, IgD, IgE, IgG or IgM) in association with a heterodimeric signaling unit comprised of Ig-α (CD79A) and Ig-β (CD79B), thereby combining antigen recognition with signal transduction [837,838]. In particular, surface IgM is a key component of the BCR and mediates intracellular signals important for proliferation or apoptosis [839]. The CD79A/B heterodimer transmits an activating signal when antigen binds to the BCR in CD20+ B-cells and in CD20-negative plasmablasts and plasma cells [840,841]. In addition, CD79A and CD79B are essential for BCR assembly and expression in human B-cells. Consequently, aberrant activation of BCR signaling plays a critical role in the pathogenesis of many B-cell malignancies. Compelling evidence suggests that B-cell malignancies arising from mature B-cells usually retain BCR expression on the surface [842]. Expression of surface Ig (sIg) appears to be critical for the majority of B-cell malignancies [843]. In agreement with previous reports suggesting that CD79A and CD79B are essential in lymphoma cell lines representing DLBCL [844,845,846], the mechanistic link between the IgM surface level and B-cell survival was recently unveiled. Through combining CRISPR/Cas9 deletion of CD79A or CD79B with studies of glycan maturation in MCL cell lines, Huse et al., demonstrated that CD79A and CD79B are equally required for surface IgM expression in human B-cells, and if one of these proteins was deleted, it causes a block in N-glycan maturation of the other CD79 protein as well as IgM, resulting in subsequent blocked transportation of the IgM complex to the plasma membrane and accumulation of immature proteins in the ER [847]. Interestingly, MCL cells usually overexpress IgM as compared to normal B-cells, which likely contribute to the pathogenesis of this lymphoma type [848]. As loss of IgM surface expression due to CD79A/B depletion reduced the survival and fitness of lymphoma cell lines, the CD79A/B signaling pathway is a potential therapeutic target. Moreover, B-CLL depends on BCR signaling for survival and proliferation [849]. As with B-cell lymphomas, surface expression of IgM has an important influence on the clinical behavior of CLL [850]. However, contrary to DLBCL and MCL, low surface expression of IgM is a characteristic feature of B-CLL [851,852,853]. Mechanistically, the impaired glycosylation and folding of the mu and CD79a chains leads to the retention of both chains in the ER and lower levels of surface IgM expression [854]. Although the t(14;18) translocation disrupts one Ig allele, expression of sIg is retained, indicating that sIg of FL is vital for tumor cell survival. Initially this retention and the ongoing somatic hypermutation led to speculation about a role for persistent antigen in FL, which was difficult to explain, given the high variability of the Immunoglobulin Variable Region (IGV) gene usage and the sequence changes resulting from somatic hypermutation. A striking observation on the nature of sIg in FL has revealed a possible explanation both for retention of sIg and for an influence of microenvironmental factors. This involves a “universal” antigen-independent mechanism able to engage sIg of all cases of FL [855]. Specifically, one of the key features of FL is the almost universal acquisition of N-linked glycosylation sites in the Ig variable region, most commonly in the Ig complementarity-determining regions (CDRs) of the heavy chains and less frequently in the light chains [856]. The acquired N-glycosylation sites are tumor-specific and are introduced during somatic hypermutation in FL [857]. Strikingly, the glycans acquired on the sIg variable region are unusual in that their biosynthetic processing terminate at the initial oligomannose-type state, indicating that they do not fully mature in the Golgi apparatus, most probably due to their inaccessibility to the appropriate Golgi enzymes [858,859]. The presence of high-mannose glycans in surface Ig elucidates the mechanism by which surface Ig may activate the malignant cells even in the absence of antigen, hence promote tumor progression. Mechanistically, mannosylated sIg (sIg-Mann) interacts with the C-type lectin dendritic cell– specific intercellular adhesion molecule 3 grabbing non-integrin (DC-SIGN) [860]. In contrast to normal B-cells, exposure of FL samples to DC-SIGN triggered prolonged phosphorylation of AKT, ERK, and phospholipase C-γ-2 (PLCγ2) and increased expression of cMYC, supporting the concept that DC-SIGN is able to activate and maintain proliferation signals that could promote disease progression [861,862]. Hence, lectins within the TME promote tumor survival and progression through antigen-independent interactions with the BCR. Interestingly, Chiodin et al., report that the same modification is seen in a subset of DLBCLs, occurring in about 50% of germinal center B-cell (GCB)-type, but only 6% of activated B-cell (ABC)-type DLBCLs and conferring poor prognosis which identifies an aggressive form of DLBCL that may be targeted therapeutically. Similar to FL, this modification facilitates a chronic antigen-independent BCR activation through interactions with microenvironmental DC-SIGN [863]. In conclusion, therapeutic approaches designed to selectively block interaction between DC-SIGN and high-mannose residues would also be of potential relevance in FL and DLBCL patients.

Immunoglobulins

As the secreted form of the BCR [864], antibodies are the most abundant glycoproteins in the blood. Antibodies are made up of two identical heavy and light chains [865] and consist of a constant (Fc for Fragment crystallizable) and a variable (Fab for Fragment antigen binding) region. While the binding specificity of the antibody is determined by the sequence and conformation of the Fab domain, its effector functions are largely determined by the Fc domain and its ability to interact with Fc receptors (FcγRs) expressed on discrete populations of immune and non-immune cells. Classical FcγRs can be broadly divided into activating or inhibitory depending on the presence of Immunoreceptor Tyrosine-based Activation (ITAM) or Inhibitory (ITIM) Motifs in the cytoplasmic tail. Interestingly, all antibodies contain glycans that are linked to conserved motifs in the Fc region which are essential for their effector functions [866,867]. Mechanistically, immunoglobulin glycans impact the effector functions of antibodies depending on the branching of N-glycans and/or the terminal sugars of N-glycans or O-glycans, which include galactose and sialic acid [868]. As the most abundant class of antibody in serum, IgG plays a central role in systemic immunity. Interestingly, IgGs are the most abundant N-glycosylated proteins in human serum with the conserved N-glycosylation site at Asn297 of their constant region [869]. These Fc glycans have a substantial impact on the structure of soluble IgG molecules; and without them IgG cannot bind to FcγRs or complement factors [870]. In a similar vein, it was shown that Siglecs limit the effectiveness of tumor-targeting antibodies by antagonizing FcγRs [871]. Notably, variation in N-glycosylation of IgG has physiological significance in hematologic malignancies. For instance, it is well-known that M-proteins from MM patients have similar structure to antibodies. Interestingly, glycosylation, based on the attachment of an oligosaccharide to M-proteins, is the most prevalent PTM of M-proteins [872]. While the exact role of Fab N-glycosylation remains poorly understood [873], recent evidence has emerged suggesting that N-glycosylation of the M-protein variable (Fab) region contributes to M-protein pathogenicity, and that it is a risk factor for disease progression of plasma cell disorders [874]. In a similar vein, M-protein glycosylation may influence the development of amyloid deposits in patients with light chain amyloidosis [875]. In fact, monoclonal light chain glycosylation has been reported as a risk factor of progression to MM and amyloidosis [876,877]. In addition, IgG N-glycan profiles can stage plasma cell disorder disease and identify patients who relapse following treatment [878]. The IgG N-glycans present at each of these stages was found to correlate disease severity with increased agalactosylated and afucosylated N-glycan content [879]. MM in remission appeared to have recovered more of the normal galactose and fucose content, closely correlating with the traditional M-protein biomarker of MM. The agalactose content subsequently increased during MM relapse. In the SMM stage, more galactose and sialic acid was observed on IgG Fc regions compared to either MUGS or MM.

Immune-related lectin receptors

Lectins, non-enzymatic, non-immunoglobulin, sugar-binding proteins, selectively interact with small subsets of the vast set of possible glycoforms and thereby facilitate diverse biological processes [880]. In particular, lectin-glycan (protein-carbohydrate) interactions serve multiple functions in the immune system [881]. In oncology, TACAs interact with Antigen-Presenting Cells (APCs) through their engagement with several lectin families of the immune system. In addition to mediating tumor cell recognition by the immune system [882], these interactions also modulate the anti-tumor innate and adaptive immune responses (immunomodulatory effects). Notably, glyco-immune interactions mediate T-cell immunosuppression. As a notable example, the interactions between endogenous lectins with two of the most abundant transmembrane glycoproteins on the T-cell surface, the CD43 and CD45, modulate several T-cell responses including migration, T-cell receptor signaling, and apoptosis in a glycan-dependent manner [883]. It is worth noting that both CD45 and CD43 are considered pan-hematopoietic markers in humans [884]. CD45, also known as protein tyrosine phosphatase receptor type C (PTPRC), is a large transmembrane glycoprotein expressed on all nucleated hematopoietic cells and an essential regulator of T- and B-cell receptor signaling through activation of various Src family kinases [885]. The leukocyte sialomucin CD43, also known as leukosialin or SPN (sialophorin), is one of adhesion inhibitory molecules that is abundantly expressed on most leukocytes [886]. In fact, there is substantial evidence for the role of glycan–lectin interactions in immunosuppressive mechanisms that occur in tumor immune escape [887,888,889,890]. Such inhibitory glycan-lectin interactions constitute glyco-immune checkpoints that circumvent the potential drawbacks of CTLA-4 and PD-1 checkpoints and offer promising novel and improved cancer immunotherapeutic modalities [891]. Furthermore, aberrant lectin binding is capable of altering critical cellular functions. For example, expression of sLeX and sLeA enables circulating cancer cells to bind C-type lectins such as endothelial E-selectin, attach to endothelial cells, infiltrate distant sites, and establish metastasis [892,893]. Human lectins are classified according to their subcellular location and the structures of the CRDs they contain [894]. The most important lectin families are the C-type lectins, the S-type lectins (galectins), and the I-type lectins (Siglecs).

C-type Lectin Receptors (CLRs)

CLRs are Ca++-dependent lectins that are defined by having one or more characteristic C-type lectin-like domains (CTLDs) [895]. CLRs on APCs facilitate uptake of carbohydrate antigens for antigen presentation, modulating the immune response in infection, homeostasis, autoimmunity, allergy, and cancer [896]. Both macrophages and B-cells can serve the antigen-presenting function. However, DCs are the superior professional APCs [897]. As professional APCs, DCs sense the microenvironment through different types of receptors to scan local environmental changes and eliminate incoming pathogens [898].
Interestingly, CLRs expressed by APCs and various non-immune cells are considered as non-classical FcRs (sometimes referred to as Type II FcR) [899,900]. CLRs can be divided into two main categories: Selectins and myeloid CLRs (expressed by cells of the myeloid lineage, such as DCs, macrophages, neutrophils, and monocytes). Both categories can function as both adhesion molecules and endocytic receptors on APCs, thus are involved in the uptake of pathogens for antigen processing and presentation, and subsequent T-cell activation [901,902,903]. Myeloid CLRs are further classified into four main groups depending on their intracellular signaling motifs [904]. Myeloid CLRs are important sensors of endogenous (self) or exogenous (non-self) that work in concert with other PRRs [905,906]. Several myeloid C-type lectins, such as DC-SIGN and MGL contribute to tumor progression by inducing immunosuppressive responses upon sensing abnormal or altered tumor-associated carbohydrates [907]. Tumor-associated glycans recognized by myeloid CLRs in immune cells possess immunomodulatory properties which enable tumor growth and immune response evasion [908]. Noteworthily, there is evidence that leukemic blasts from B-ALL and T-ALL patients have increased binding with myeloid C-type lectins thereby affecting their immunological elimination [909]. The most important molecules from the C-type lectins family include:

Myeloid C-type lectin receptors:

The Macrophage Galactose-type Lectin (MGL, CD301; also known as CLEC10A): MGL is a Type II C-type lectin, and is the only lectin that exclusively binds terminal GalNAc residues [910]. MGL is typically expressed by immature DCs and alternatively activated macrophages (subtype M2a) conferring immunesuppressive (tolerogenic) signaling. The main ligands of MGL in cancer are truncated O-glycans including the Tn antigen (α-GalNAc-Ser/Thr) [911,912], the TF antigen (Galβ1–3GalNAc) [913], sTn [914], as well as N-GalNAc and galactose and core 2 structures [915,916]. Interestingly, MGL is the only C-type lectin receptor that recognizes and exhibits a high binding specificity for terminal α- and β-linked GalNAc residues found in Tn, sTn and LacdiNAc antigens [917,918]. Strikingly, the binding of MGL to altered glycosylation prevents an anti-tumor immune response, allowing cancer cells to escape the immune system. In this context, the expression of Tn antigen on tumor cells engaging MGL on APCs creates an immunosuppressive milieu. This suggests that the MGL-Tn axis is an immunosuppressive checkpoint axis in cancer [919,920]. Mechanistically, Tn antigen engagement by MGL results in the polarization of tolerogenic DCs and immunosuppressive macrophages [921,922,923]. In addition, MGL upregulation on tolerogenic DCs contributes to dampening T-cell immunity in an MGL-dependent manner through interacting with a Tn antigen on the CD45 molecules of effector T-cells. This binding suppresses the phosphatase activity of CD45 and inhibits lymphocyte protein tyrosine kinase (Lck) activation. In effector T-cells, CD45-mediated dephosphorylation of the C-terminal tail of Lck leads to the formation of its active form, which in turn is required for the initiation of T-cell receptor (TCR) signaling [924,925]. Therefore, the suppression of CD45 activity by MGL reduces TCR signaling pathways, thus leading to the inhibition of T-cell proliferation, reduction in proinflammatory cytokine synthesis, and, therefore, the acceleration of T-cell apoptosis [926,927,928]. On the other hand, binding of MGL to its ligands contributes to immune suppression by increasing IL-10 (an anti-inflammatory cytokine) secretion and induction of T-cell apoptosis [929]. Further, owing to its specificity for the truncated O-glycans, MGL is able to recognize the mucin MUC1. A study performed by Napoletano et al., showed that the interaction of MGL with the Tn-MUC1 glyco-peptide, with a high density of glycans (15 Tn residues), was stronger than MUC1 bearing lower amounts of GalNAc residues [930]. The binding of MGL to the truncated glycan structures on MUC1 leads to a defective T-helper (Th) cell-mediated response as well as to a reduction of cytotoxic T lymphocytes (CTLs) [931]. Besides, the tumor-associated MUC1 glycoform bearing the sialyl TF antigen was shown to impair the DC function by enhancing spontaneous apoptosis or defective antigen presentation [932]. Therefore, the MGL-Tn-CD45 and the MGL-Tn-MUC1 represent novel immunosuppressive checkpoint axes, especially in context of modulating the APC functions. In addition, the T-cell leukemia model cell line Jurkat is known to have a high level of Tn antigens (due to a mutation in Cosmc) which rendered acute T-cell leukemia cells a model system to study the immunoregulatory properties of MGL and the effect of its ligand recognition [933]. Both CD43 and CD45 have been described as the main carriers of the Tn antigen interacting with MGL in Jurkat cells [934]. Therefore, it can be inferred that both the Tn antigen and the MGL-Tn-CD43/ MGL-Tn-CD45 axes are potential therapeutic targets for treatment of T-ALL.

The Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Non-integrin (DC-SIGN, CD209): Similar to the MGL, DC-SIGN belong to the type II group of CLRs and is expressed on APCs (mainly immature DC and macrophages with M2 polarization) [935,936]. DC-SIGN is associated with antigen uptake and subsequent MHC (major histocompatibility complex) presentation for the potentiation of adaptive immune responses [937,938,939,940,941]. DC-SIGN is known to bind the tumor-associated Lewis antigens (LeX, LeY, LeA, LeB) [942,943]. DCSIGN is involved in tumor immune evasion as well as promoting tumor development [944,945]. Mechanistically, the interaction between DC-SIGN with Lewis X (LeX; CD15) antigens on tumor cells leads to immune suppression through various mechanisms driven by TAMs, including increased PD-L1 expression [946,947]. As an example, the expression of DC-SIGN on DCs binds to LeX and LeY carbohydrates on tumor-associated carcinoembryonic antigens of colon cancer cells, suppressing the function of antitumor immunity of DCs and subsequently inducing immune evasion, which is in favor of the progression and metastasis of colon cancer cells [948,949]. In this context, CD15 was shown to be the ligand for DC-SIGN in some ALL cells. However, other ligands play a role in the interaction of ALL cells with DC-SIGN. It should be noted that B-ALL cells demonstrated increased binding to DC-SIGN and L-SIGN (liver/lymph node- SIGN, also called DC-SIGN-related or CD299), which correlated with poor prognosis, suggesting involvement of this interaction in pathogenesis [950]. Importantly, blockade of DC-SIGN can abrogate immunosuppressive activity from TAMs and increase anti-tumor activity of CD8+ T-cells, while working synergistically with PD-1 immunotherapies in vitro [951]. In addition, BCRs in several B-cell malignancies carry high-mannose oligosaccharides, which interact with mannose-binding lectins, especially with DCSIGN, in the TME and initiate antigen-independent signaling that may drive tumor growth/survival. This lectin interaction with the BCR is critical for lectin-driven malignancies, particularly FL. At instance, the acquisition of new glycosylation motifs in the BCR due to gene rearrangement and/or somatic hypermutation is an early event in the genesis of FL [952]. In fact, most FL cases express a BCR that has acquired ≥1 N-linked glycosylation motifs (N-motifs) in their Fab portions by somatic hypermutation [953]. These N-motifs contain mannose-terminated glycans and can interact with lectins in the TME, activating the tumor BCR pathway [954,955,956]. However, insertion of N-glycosylation sites in Ig variable region genes has been detected in other germinal center (GC)-associated lymphomas, specifically in subsets of DLBCL and BL, suggesting involvement of altered glycans in pathogenesis of these malignancies as well. Strikingly, the BCR in CLL also carries high-mannose oligosaccharides, albeit in the heavy chain constant rather than variable region. The high expression level of the unique glycoform, particularly in the more aggressive unmutated CLL subset, suggests a functional significance for this glycan in CLL. Hence, targeting BCR-lectin interaction is considered to be an interesting therapeutic strategy [957].

The Myeloid Inhibitory C-type Lectin-like Receptor (MICL; also known as CLL-1, CLEC12A, DCAL-2, and KLRL-1): Like MGL, MICL, also known as human C-type lectin-like molecule-1 (CLL-1), is a myeloid cell-expressed C-type lectin. Since it is overexpressed in over 90% of AML blasts and the majority of LSCs while absent on normal HSPCs, CLL-1/CD371 is a potential target for immunotherapy in AML [958,959]. Currently, researchers from the Memorial Sloan Kettering (MSK) cancer center are studying a new CAR T-cell therapy (CD371-CAR-IL18) that targets CLL-1 to treat AML (NCT06017258).

Selectins

Selectins belong to group IV of the CLRs. They play crucial roles in regulating the trafficking of leukocytes. These proteins are responsible for the initial capture (i.e., “rolling”) of leukocytes from the circulation before extravasation across the vascular endothelium can occur. Selectins share a common ligand, the carbohydrate sLe^X, though their affinity is modulated by the nature of the carbohydrate scaffold and the backbone that carries sLe^X [960]. Each selectin is named according to its expression pattern. Overall, E-selectin (CD62E) binds leukocytes to activated endothelium, whereas P-selectin (CD62P) binds leukocytes to platelet-activated endothelium and platelets, and L-selectin (CD62L) binds leukocytes to lymph node HEVs. Broadly, selectins can be divided into two functional categories:

1. The interactions between P- and E-selectins with their ligands mediate leukocyte homing into non-lymphoid tissues in response to inflammation or tissue injury [961,962]. While P-selectin is stored in endothelial cell Weibel-Palade bodies and platelet storage granules, E-selectin expression is limited to endothelial cells but is not stored in any intracellular compartment. Hence, endothelial E-selectin expression is driven by inflammatory cytokines, whereas P-selectin secretion occurs via exocytosis of endothelial stores after stimulation by activated platelets [963,964]. P- and E-selectin ligands have a sLe^X which contains a sialic acid bound to the terminal galactose of the Lewis antigen in an α2-3 linkage, catalyzed by the ST3GAL family of enzymes [965]. However, P-selectin recognizes with high affinity sLe^X presented on Core2 O-glycans carried on threonine 57 of PSGL-1 [966].

2. L-selectin is a type-I transmembrane glycoprotein and cell adhesion molecule that is expressed on most circulating leukocytes [967]. Intriguingly, L-selectin-ligands interactions mediate steady-state lymphocyte homing into secondary lymphoid organs. As a matter of fact, lymphocyte homing is regulated via adhesive interactions between lymphocytes and 6-sulfo-sLe^X on HEVs. Mechanistically, the first interaction between naive lymphocytes and HEVs (specialized blood vessels mediating lymphocyte trafficking to lymph nodes and other secondary lymphoid organs) is initiated by lymphocyte L-selectin that recognizes a family of sulfated mucin-like glycoproteins known as HEV sialomucins including glycosylation-dependent cell adhesion molecule-1 (GlyCAM-1), CD34, podocalyxin, endoglycan, endomucin, and nepmucin which become effective L-selectin ligands when they are modified with 6-sulfo sLe^X structures by a group of glycosyltransferases and sulfotransferases highly expressed in HEV endothelial cells (HECs) [968]. Indeed, the expression of high levels of the L-selectin-binding HEV-specific glycoforms of HEV sialomucins is undoubtedly one of the most important features of the HEV endothelium [969].

Within this context, the tetrasaccharide 6-sulfo-sLe^X, abundantly produced in HEVs and present on both N-glycans and extended core 1 and 2 O-glycans decorating HEV sialomucins [970,971,972], is the critical carbohydrate determinant for L-selectin recognition [973,974,975]. Consequently, it has been reported that GlcNAc6STs can control lymphocyte homing via the ligand 6-sulfo-sLe^X synthesis on HEVs [976]. Noteworthily, L-selectin ligands expressed on HEVs in peripheral lymph nodes are collectively referred to as peripheral node addressin (PNAd), which is defined by its reactivity to the HEV-specific mAb “Mouse Endothelial Cell Antigen-79” (MECA-79) [977,978]. In fact, MECA-79 is a fantastic tool for HEV studies that specifically recognizes 6-sulfo sLe^X structures on extended core 1 O-glycans [979]. In addition, selectins have a key role in trafficking of T-cells to tissues. L-selectin controls the capacity for naive and memory T-cells to actively survey peripheral lymph nodes, whereas P- and E-selectin capture activated T-cells on inflamed vascular endothelium to initiate extravasation into non-lymphoid tissues. The capacity for T-cells to interact with all of these selectins depends on the enzymatic synthesis of complex O-glycans, and thus, this protein modification plays an indispensable role in regulating the distribution and homing of both naive and previously activated T-cells in vivo [980].

The best characterized selectin ligand is P-selectin glycoprotein ligand-1 (PSGL-1) that is mostly expressed on the surface of all leukocytes where it facilitates rolling and tethering [981]. All three selectins bind to PSGL-1. However, binding of PSGL-1 to P-selectin (CD62P), but not E-selectin, is dependent on posttranslational modifications. P-selectin requires a very specific glycopeptide epitope to engage its glycoprotein partner PSGL-1. This epitope includes sLe^X on a core 2 residue with nearby sulfated tyrosine [982,983,984]. PSGL-1 represents a marker of plasmacytic differentiation since it is constantly expressed in MM cells as well as in lymphoproliferative disorders showing plasmacytic differentiation [985]. Importantly, interactions between PSGL-1 and P- and E-selectin regulate MM cell proliferation and homing and contribute to resistance to therapies [986]. PSGL-1 is also essential for hematogenous metastasis of lymphomas [987]. PSGL-1 can bind to V-domain immunoglobulin suppressor of T-cell activation (VISTA) to mediate T-cell suppression in acidic environments, characteristic of many TMEs [988]. Consequently, blockade with antibodies specific to this PSGL-1/VISTA axis reversed immunosuppression in vivo, and ongoing clinical trials are assessing the blockade of VISTA. In light of these findings, PSGL-1 could also be a promising therapeutic target to overcome T-cell suppression [989,990]. Physiologically, selectins are important for the interactions involving leukocytes, platelets, or endothelial cells [991]; and therefore, they play an essential role in tumor-promoting inflammation and cancer metastasis. During the metastatic cascade, adhesion of circulating cancer cells to the walls of blood vessels is the function of selectins [992]. Notably, the role of E-selectin/ligand (sLeX and sLeA) interactions in initiating and enhancing the adhesion of cancer cells to the endothelium in tumor metastasis is well established [993]. For instance, it has also been shown that E-selectin drives cancer metastasis into the BM [994,995]. Noteworthily, Connolly et al., suggested that aberrant transcription of glycosylation genes, involved predominantly in selectin ligand synthesis, is associated with inferior survival outcomes and may help identify patients likely to benefit from treatment with agents targeting aberrant glycosylation, e.g., E-selectin inhibitor in MM [996]. It is important to note that binding of E-selectin to a cell requires the presence of sLe^X or sLe^A tetrasaccharides at the termini of cell surface glycolipids, or glycoprotein O-glycans (Ser/Thr-linked) or N-glycans (Asn-linked) [997]. Strikingly, P-selectin and L-selectin-mediated interactions also contribute significantly to tumor metastasis (both are essential for creating an inflammatory metastatic microenvironment once cancer cells intravasate and circulate in the bloodstream) [998,999]. In this vein, accumulating evidence indicates that P-selectin-mediated interactions contribute to cancer progression [1000,1001].

S-type lectins (Galectins)

Galectins – previously known as “S-type lectins” and then named “galectins” in 1994 – constitute an evolutionary conserved family of β-galactoside-binding lectins composed of one or two carbohydrate-recognition domains (CRDs). Unlike Siglecs and selectins (mostly cell-surface-bound receptors), galectins are soluble lectins [1002]. Since their discovery in the 1970s, their biological roles, initially thought to be limited to recognition of carbohydrate ligands in embryogenesis and development, have expanded in recent years by the discovery of their immunomodulatory activities [1003]. The minimal structure recognized by galectins is the disaccharide N-acetyllactosamine (LacNAc), which is found in N-glycans and O-glycans and can be presented as multiple units (poly-LacNAc) on cell surface glycoconjugates [1004]. LacNAc is 5–10 times more active than lactose [1005,1006], and so N-glycans are good ligands for most galectins. However, substantial differences exist in the glycan-binding preferences of individual members of the galectin family, particularly in the recognition of sialylated and sulfated glycans [1007], which might be the basis of functional differences in their biological activity [1008]. The extent of N-glycan branching, the multiplicity of LacNAc residues and/or modifications (e.g., sialylation or fucosylation) on LacNAc or poly-LacNAc structures may alter galectin-glycan interactions [1009]. For instance, incorporation of α2-6-linked sialic acid to cell surface glycoconjugates interrupts binding of some members of the family, including galectin-1 [1010]. Of particular interest, the affinity of galectins for N-glycans increases in correlation with β1-6 branching (mediated by GnT-5/MGAT5) and extension with poly-LacNAc. Galectins are expressed in a plethora of tissues and cell types, and their functions are highly context-dependent [1011]. In contrast to other chemokines, cytokines, or transcription factors, galectins mediate a multitude of vital activities through binding to the outermost grouping of carbohydrates on a glycoprotein or glycolipid oligosaccharide rather than specific receptors [1012]. Nevertheless, galectins are peculiar in that they also mediate their functions intracellularly. There is compelling evidence that galectins might have noncarbohydrate binding partners and functions. These CRD-independent functions have been particularly well documented for the intracellular galectins [1013,1014,1015]. By contrast, an important mechanism by which extracellular galectins regulate cellular events is by complexing with cell surface glycoprotein receptors to create galectin–glycoprotein lattices [1016]. These lattices are vital for organization of glycoprotein assemblies on the cell surface [1017] as well as signaling [1018]. Mechanistically, lattices can affect cell signaling in several ways. Galectin lattices can retain glycoproteins on the cell surface by retarding endocytosis and thus increase the effective concentration of the receptor, or galectins can alter signaling by the receptors [1019]. For instance, galectin-glycan lattice is known to regulate BCR signaling in lymphocytes. It is worth noting that in relation to BCR signaling, both BCR and CD45 are modified by N-glycans and act as galectin ligands. Interestingly, BCR interacts with CD45 (a ligand for both galectin-3 and galectin-1) through galectin bridging between the BCR and CD45. Since BCR signaling is known to be involved in cell adhesion or migration, interaction between CD45 and BCR through the glycan-galectin lattice might be a foundation of BCR-mediated cell adhesion mechanism [1020]. In cancer, galectins play central roles in tumor progression as well as they are excellent negative regulators (checkpoints) of the immune cell functions, participating in the creation of a TME that promotes tumor escape [1021]. In the TME, the abundantly expressed galectins play essential role in the modulation of the antitumor immune response by regulating the innate and adaptive immune systems [1022,1023,1024]. In addition, galectins are also crucial for RTK activation; the altered glycosylation changes observed in RTKs are known to allow galectin recognition (mainly galectin-1, -3, and -9) [1025]; the latter are responsible for oncogenic activation of RTKs. Mechanistically, cancer cells utilize extracellular galectins to induce lattices on the cell surface where activated growth factor receptors are trapped which leads to sustained activation of the signaling pathways by preserving a constant flow of proliferative stimuli. Hence, the RTK-galectin interplay constitutes an attractive target for development of anticancer therapies [1026]. Amongst the 12 galectins identified in humans so far, galectin-1, galectin-3, and galectin-9 were most intensively studied in context of cancer [1027]. Table-4 outlines the multiple roles of these galectins in hematologic malignancies. Noteworthily, galectin-1, -2 and -3 have important roles in the regulation of the adaptive immune response [1047]; particularly in T-cell activation and B-cell differentiation [1048]. Galectin-1 and -3 are expressed by most cell types in nearly every tissue [1049,1050], whereas galectin-9 is mainly expressed by gastrointestinal epithelial cells, the thymus and endothelial cells [1051,1052,1053]. These galectins are strongly implicated in cancer progression and immune escape; the latter is mediated by regulating T-cell activation and T-cell exhaustion [1054]. Indeed, galectin-1, -3, and -9 can all regulate T-cell death. Galectin-1 regulates T-cell death only via the extracellular route. By contrast, galectin-3 regulates cell death, both intra- and extracellularly. In this context, galectin-3 is the only family member with both pro- and antiapoptotic activity: extracellular galectin-3 directly induces death of human thymocytes and T-cells, while intracellular galectin-3 blocks T-cell death (i.e., anti-apoptotic) [1055]. Mechanistically, the human TCRα/β-CD3 complex has 12 N-glycan sites [1056]. N-glycans on TCR bind both galectin-1 and galectin-3 [1057]. The galectin-glycoprotein lattice strengthened by GnT-5/ MGAT5-modified glycan negatively regulates T-cell activation thresholds by inhibiting ligand-dependent TCR clustering at the immune synapse (T-cell activation requires clustering of a threshold number of TCRs at the site of antigen presentation). Consequently, a deficiency in GnT-5/MGAT5, the enzyme crucial in the N-glycosylation pathway, lowers the T-cell activation threshold by enhancing TCR clustering [1058]. On the other hand, galectin-9 induces T-cell death by mechanisms distinct from galectin-1 or -3 [1059,1060]. Furthermore, galectins were found to augment T-cell exhaustion induced by T-cell exhaustion markers/immune checkpoint receptors [1061]. For example, the engagement of galectin-3 and PD-1 leads to tumor-induced immune suppression, and both PD-L1 and galectin-3 have been implicated in M2-macrophage polarization and reduced CD8+ T-cell recruitment to the tumor site [1062]. Galectin-9 also interacts with PD-1 which attenuates galectin-9/TIM-3-induced T-cell apoptosis. This dual effect establishes galectin-9 as an important regulator of tumor immune response that can be targeted for cancer immunotherapy [1063]. In addition, some exhaustion markers are known ligands for galectins. Galectin-3 modulates the threshold of T-cell activation through binding to CTLA-4 and LAG-3/CD223 (lymphocyte activation gene 3) [1064,1065]. Noteworthily, LAG-3 is essential for galectin-3- mediated suppression of CD8+ T cell-secreted interferon gamma (IFNγ) in vitro (the capability of galectin-3 to bind activated antigen-committed CD8+ T-cells in the TME is only possible through galectin-3 binding to LAG-3 [1066,1067,1068]. Moreover, it is recognized that galectin-9 is a ligand for TIM-3/CD366 (T-cell immunoglobulin and mucin-domain containing-3) [1069]; the latter plays a functional role in establishing T-cell exhaustion and is highly implicated in the regulation of anti-tumor immunity [1070].Hence, galectin-9–TIM-3 interaction is being developed as a new target for checkpoint blockade in cancer immunotherapy [1071]. To sum up, galectins have emerged as regulatory glycocheckpoints that control anti-tumor immunity by inducing T-cell exhaustion [1072,1073]. That said, the immunomodulatory role of these galectins has drawn attention to the possibility of targeting them and/or their ligands to overcome the mechanisms of tumor immune escape [1074,1075]. Within this context, literature indicated that galectin inhibition induces effective antitumor effects, especially when combined with other strategies (e.g., irradiation, anti-angiogenic, chemotherapies, etc.). In addition, galectin inhibition alone or in combination with ICB is an attractive therapeutic strategy to reverse the immune escape mechanisms induced by T-cell inhibition [1076,1077,1078]. One of the first attempts to use galectin inhibitors in cancer consisted of administering a β-D-lactosyl-steroid with antimigratory activity (i.e., with antimetastatic and/or anti-invasive effects). This treatment significantly increased the survival of mice grafted with lymphoma and glioblastoma cells [1079,1080]. β-D-lactosyl-steroid belongs to a class of molecules capable of binding to the CRD and thus preventing further ligand binding. Galectin inhibitors based on these competitive interactions include thiodigalactose (TDG) which underwent chemical modifications to improve its inhibitory properties. The most advanced TDG in clinical studies is TD139 (also called GB0139, developed by Galecto Biotech) which was initially evaluated in pre-clinical models of lung fibrosis [1081,1082]. TD139 recognizes galectin-3 CDR with high affinity (Kd 68 nM) but its absolute selectivity for galectin-3 is relative since it also binds to galectin-1 CDR (Kd 220 nM) and other galectins with lower affinities [1083]. Zetterberg et al., discovered a new class of 1,3-substituted α-d-monogalactopyranosides with surprisingly high affinity for galectin-3 [1084]. In this series, GB1107 and GB1211 (shares a chemical template with GB1107) have good affinity (Kd 37 nM) and bind to the CRD of galectin-3. In contrast to GB0139, which has limited oral bioavailability, GB1107 is characterized by good biodisponibility upon oral administration [1085]. Mechanistically, GB1107 promotes tumor M1 macrophage polarization and CD8+ T-cell infiltration. In addition, GB1107 potentiated the effects of a PD-L1 immune checkpoint inhibitor to increase expression of cytotoxic (IFNγ, granzyme B, perforin-1, Fas ligand) and apoptotic (cleaved caspase-3) effector molecules [1086,1087]. Furthermore, the Modified Citrus Pectin (MCP), which is obtained by partial hydrolysis of citrus pectin, is one of the most studied galectin inhibitors. In vitro studies demonstrated that MCP binds galectin-3 through galactoside residues [1088,1089]. However, due to the high chemical variability of dietary MCP supplements on the market, more defined MCP variants have been described including: PectaSol-C, GCS-100, GM-CT-01 and GR-MD-02. Noteworthily, GCS-100 is a complex polysaccharide prepared from MCP and has been shown to have great potential to treat MM cells, including those resistant to dexamethasone, melphalan, or doxorubicin by La Jolla Pharmaceuticals. Mechanistically, GCS-100 detaches galectin-3 from CD4+ and CD8+ tumor-infiltrating lymphocytes, boosts cytotoxicity and restores IFNγ secretion [1090]. Interestingly, the biological effects of both MCP and GCS-100 are carbohydrate-dependent. Unfortunately, La Jolla Pharmaceuticals announced that they were discontinuing the development of GCS-100 in 2015 after the FDA required a more complex characterization of the compound to advance into late-stage development (NCT00776802 and NCT00609817). The details of galectin inhibitors are beyond the scope of this article but are reviewed elsewhere [1091].

Note: MM, Multiple myeloma; CLL, Chronic lymphocytic leukemia; R/R HL, relapsed/refractory Hodgkin lymphoma; KMT2A, Histone-lysine N-methyltransferase 2A; KMT2A-rearranged, KMT2A-R; BM, bone marrow; B-ALL, B-cell precursor acute lymphoblastic leukemia; L-CTCL, Leukemic cutaneous T-cell lymphoma; Th1, type 1 T helper T cells; Th2, type 2 helper T cells; MSCs, mesenchymal stromal cells; TME, tumor microenvironment; AML, Acute myeloid leukemia; GCS-100, a modified pectin inhibitor of galectin-3; ABT-199, a BH3 mimetic; Ara-C, cytosine arabinoside; BH3, Bcl-2 homology 3; FLT3-ITD, FMS-like tyrosine kinase-3 internal tandem duplication; HMCLs, inter-human myeloma cell line; BMSCs, bone marrow stromal cells; VEGFA, vascular endothelial growth factor A; DLBCL, Diffuse large B cell lymphoma; JNK, Jun N-terminal kinase (also known as stress-activated protein kinase, SAPK) is one of the 3 major members of the mitogen-activated protein kinase (MAPK) superfamily; the others are extracellular signal-regulated kinase (ERK) and the p38 MAP kinase; TIM-3, T cell immunoglobulin and mucin-domain containing-3; NK cells, natural killer cells.

Table 4: The multiple roles of galectins in hematologic malignancies

Galectin-1

Human galectin-1 is a 14-kDa protein that contains 135 amino acids and is encoded by the LGALS1 gene [1092]. Galectin-1 is a proto-type member of the galectin family with a single CRD that was first discovered in 1975 after isolation from an electric eel, and thus, named “electrolectin” [1093]. Galectin-1 has protumorigenic activity. Given that the immunosuppressive TME is one of the major culprits accounting for the progression of cancer, galectin-1, an immunosuppressive biomarker, has received a great deal of attention. Mechanistically, cancer cells hijack galectin-1 to evade immune surveillance. That galectin-1 is a critical determinant of T-cell apoptosis has been demonstrated since 1995; and hence, targeting galectin-1 possesses a potent efficacy in immune-associated diseases from experimental data, such as cancer [1094]. In this context, elevations of galectin-1 in the TME were well documented in various malignancies [1095], including lung and pancreatic carcinoma, melanoma, and neuroblastoma [1096,1097,1098]. Three glycoprotein counterreceptors, CD43, CD45, and CD7 are involved in T-cell death induced by galectin-1 [1099,1100,1101,1102]. While the expression of CD7, a small glycoprotein that is exclusively N-glycosylated, on human T-cells is essential for galectin-1-induced T-cell apoptosis [1103], expression of both CD43 [1104] and CD45 [1105] enhances (but is not required for) apoptosis induced by galectin-1. Interestingly, CD45-galectin-1-induced T-cell death is dependent on the relative amount and type of glycans present on these glycoproteins. Mechanistically, core 2 O-glycans provide galectin-1-binding moieties to induce the clustering of CD45 and T-cell death [1106,1107]. Furthermore, galectin-1 binding to N-glycans in general and to N-glycans on CD45 in particular (CD45 bears abundant N-glycans) is required for galectin-1 signaling and T-cell death. N-acetyllactosamine (Galβ1–4GlcNAc) that is not capped by α2,6-linked sialic acid (found on branched core 2 O-glycans and abundant on N-linked glycans) is the preferred minimal saccharide ligand bound by galectin-1. As this disaccharide is ubiquitously expressed on a variety of cell surface glycoproteins, galectins bind N-acetyllactosamine, with avidity increasing in proportion to the number of N-acetyllactosamine units i.e. GlcNAc branching (galectins do not bind soluble lactosamine disaccharides). This entails that glycans must contain multiple N-acetyllactosamine units in order to bind galectin-1 with high avidity (galectin-1 preferentially binds glycoproteins containing linear Poly-N-acetyllactosamine sequences) [1108,1109,1110,1111,1112]. Furthermore, the regulated expression of glycosyltransferases during development and activation, creating N-acetyllactosamine ligands, may determine T-cell susceptibility to galectin-1-induced cell death [1113]. In this context, the expression of the GCNT1 (which creates a branched structure on O-glycans that can be elongated to present multiple lactosamine sequences) is required for galectin-1 mechanism of inducing T-cell death [1114]. Conversely, galectin-1-induced T-cell death is inhibited by the expression of ST6GAL1 that preferentially utilizes N-glycans as acceptor substrates [1115,1116] resulting in increased sialylation of N-glycans on CD45 (CD45 is an established acceptor substrate for ST6GAL1). Interestingly, sialylation of core 1 O-glycans also antagonizes susceptibility to galectin-1-induced cell death [1117]. Noteworthily, core 2 O-glycan expression is only required for galectin-1 T-cell death if the cells express CD45. Mechanistically, core 2 O-glycans was essential for the galectin-1-induced reduction in CD45 phosphatase activity that is necessary for galectin-1 T-cell death. However, changes in glycosylation of CD45, rather than the expression level of CD45, may be the primary factor that regulates susceptibility to galectin-1 death during thymocyte development [1118]. On the other hand, CD43, which is heavily O-glycosylated, contributes a significant fraction of galectin-1 binding sites on T-cells, as T-cells lacking CD43 bound approximately 50% less galectin-1 than T-cells expressing CD43. While galectin-1 binds to both N-glycans and O-glycans on CD45, O-glycosylation is primarily responsible for galectin-1 binding to CD43 (CD43 bears only a single N-glycan). Surprisingly, galectin-1 can bind to core 1 O-glycans on CD43 even in the absence of core 2 O-glycan modifications (addition of core 2 O-glycans specifically to CD43 is not essential for galectin-1 death) [1119]. Despite that lactosamine is not present in core 1 O-glycans and the affinity of galectin-1 for isolated Galβ1,3GalNAc sequences found in core 1 O-glycans was 125- fold lower than for Galβ1,4GlcNAc (lactosamine) sequences [1120], galectin-1 is able to bind the extracellular domain of CD43 decorated with either core 1 O-glycans or core 2 O-glycans with roughly equivalent affinities leading to activation of apoptotic signaling [1121]. In this case, low affinity/high avidity binding to a highly abundant but less preferred glycan ligand, Galβ1,3GalNAc, is sufficient to induce T-cell death.

Although T-cells dying in response to galectin-1 display characteristics common to other death pathways, galectin-1 does not trigger death via known T-cell surface apoptotic triggers such as Fas or CD3 [1122,1123]. As a negative regulator of T-cell activation and survival, galectin-1 plays a critical role in promoting escape from T cell-dependent immunity, thus conferring immune privilege to tumor cells that leads to tumor development and progression [1124]. Within this context, tumor-secreted galectin-1 mediates immune evasion by preventing T-cell migration into the tumor. Mechanistically, galectin-1 reprograms the tumor endothelium to upregulate cell-surface PD-L1 and galectin-9 [1125]. Although the immune-inhibitory effects of galectin-1 have been primarily attributed to the modulation of T-cells, galectin-1 also induces a TAM-like phenotype with a combination of pro-inflammatory features and upregulation of immunomodulators such as checkpoint protein PD-L1/CD274 and the indoleamine 2,3-dioxygenase-1 (IDO1) [1126]. Intriguingly, galectin-1 may promote survival of hematological malignancies through direct action on tumor cells but also through effects on the TME. High galectin-1 expression was reported in KMT2A-R B-ALL and HL [1127,1128]. In B-ALL, galectin-1 is a highly sensitive and specific biomarker of KMT2A rearrangement that is likely induced by a KMT2A-dependent epigenetic modification [1129]. Recently, Li et al., identified galectin-1 as a striking biomarker of progression to MF and poor survival in multiple patient cohorts. Interestingly, galectin-1 inhibition ameliorated disease features with a similar impact on splenomegaly and myeloproliferation to JAK-inhibition, reducing myeloproliferation and fibrosis in vitro and in vivo. Likewise, a clear correlation between LGALS1 expression level and poor survival was found in AML, suggesting a role beyond MPN. Therefore, galectin-1 inhibition is a promising therapeutic strategy in both myeloid malignancies [1130]. Taken together, galectin-1 inhibitors represent an attractive opportunity in order to suppress tumor growth and progression by thwarting tumor-immune escape, attenuating aberrant angiogenesis and circumventing resistance to anti-cancer therapies [1131].

Galectin-3

Galectin-3 is a central regulator of cell adhesion and inflammation in cancer. Human galectin-3 is a 35-kDa protein that contains 135 amino acids and is encoded by the LGALS3 gene [1132]. Like galectin-1, the preferential glycan ligand for galectin-3 is Poly-N-acetyllactosamine (poly-LacNAc); but unlike galectin-1, galectin-3 binding ability does not require a terminal β-galactose residue [1133]. An alternative to Poly-LacNAc chains is a chain composed of LacdiNAc glycan units [-3GalNAcβ1-4GlcNAcβ1-] n generated by the action of a β1-4GalNAc-transferase [1134].  LacdiNAc, a recently identified epitope in some O- and N-linked glycoproteins, can act as a selective galectin-3 ligand [1135]. Interestingly, terminal LacdiNAc expression on glycosylated proteins has been reported to be upregulated in a variety of malignancies, suggesting its potential value as a cancer glycome biomarker [1136]. Again, sialylation is a major regulator of galectin-3–glycan ligand binding (inhibited by the action of ST6GAL1) [1137]. In a similar vein, the expression of sTn on O-glycans, a biosynthetic product of ST6GALNAC1, was able to decrease cell surface galectin-3 and galectin-3-binding sites leading to an accumulation of galectin-3 in the intracellular environment, which can account for the chemotherapeutic resistance observed in ST6GALNAC1-overexpressing tumor cells [1138].

Galectin-3 role in immunosuppressive TME

Although both galectin-1 and galectin-3 can bind to T-cells and trigger T-cell death [1151,1152], these galectins induce two separate death pathways with distinct mechanisms. Notably, galectin-3 binds to a complement of T-cell surface glycoprotein receptors that differ from those recognized by galectin-1. CD45 and CD71, but not CD29 and CD43, contribute to galectin-3-induced T-cell death. Although CD45 is not required but regulates susceptibility to galectin-1, CD45 is required for galectin-3 cell death. By contrast, CD7 is not required for death triggered by galectin-3 [1153]. Unlike galectin-1 binding that result in clustering of CD45 during galectin-1-induced T-cell death [1154], galectin-3 induces clustering of CD71, but not CD45, on the T-cell surface. Instead, galectin-3 binding creates small patches of CD45 around the cell surface. In addition, galectin-3 has been proposed to separate CD45 and TCR into discrete domains on the T-cell surface during T-cell activation [1155].

Similar to galectin-1, specific glycosylation of CD45 is important for regulation of galectin-3-mediated signaling. GCNT1 (C2GnT1) regulates galectin-3 binding to a subset of highly glycosylated CD45 glycoforms. In addition, galectin-3 has high affinity for β-1,6-N-acetylglucosamine branched glycans (complex N-glycans) formed by GnT-5/MGAT5 modification [1156]. Increased branching of N-glycans can directly inhibit T-cell activation by GnT-5/MGAT5-dependent galectin-3 interaction [1157]. Mechanistically, β1,6GlcNAc-branched N-glycans attached to the TCR enhance binding to galectin-3, an interaction that limits TCR clustering at sites of immune synapse by restricting lateral TCR movement within the plane of the membrane, thus increasing agonist thresholds for TCR signaling (i.e., reducing TCR signaling) [1158,1159,1160], and vice versa; β1,6GlcNAc-branching deficiency in naive T-cells reduces activation thresholds by weakening the galectin lattice, enhancing TCR clustering, and signaling at the immune synapse [1161].

Furthermore, galectin-3 inhibits TCR-mediated activation of CD4+ T-cells, by affecting the early events in signal transduction and potentiating down-regulation of TCR in cells activated by engagement of the receptor leading to lower levels of cytokine production [1162]. As a result, galectin-3 binding to the TCR in the immunological synapse is an important immunosuppressive mechanism in the TME, which highlights the potential use of galectin-3 as a therapeutic target capable of modulating antitumor immunity [1163]. Within this context, the galectin-3 ligand LAG-3 expression in the TME correlates with poor prognosis in MM and several hematologic malignancies [1164,1165]. Mechanistically, galectin-3 negatively regulates T-cell function and proliferation through interaction with LAG-3, especially on CD8+ CTL, possibly by reducing the affinity of the T-cell receptor and its internalization. A phase I/IIa trial aiming at evaluating the safety and efficacy of LAG-3 blockade with Relatlimab, BMS- 986016 (the first developed anti-LAG-3 mAb) with or without Nivolumab (PD-1 inhibitor) in the setting of refractory or recurrent B-cell malignancies including NHL, CLL, HL and MM has already been completed (NCT02061761). Another phase I/ II randomized trial (NCT04150965) designed to evaluate anti- LAG-3 and anti-TIGIT (T-cell immunoreceptor with Ig and ITIM domains), in order to understand their immunologic effects and safety both as single agents and in combination with pomalidomide and dexamethasone, in patients with R/R MM is currently underway.

Strikingly, CD45 is the major receptor tyrosine phosphatase in B-cells. Not surprisingly, the BCR interacts with CD45 through galectin bridging between the BCR and CD45. Interestingly, CD45 regulates BCR and TCR activation in different ways: the higher level of CD45 favorably affects BCR signaling, unlike for TCR. Notably, the importance of CD45 synthesis by tumor cells in predicting the clinical outcome of patients with CLL, ALL, MM, and DLBCL has already been stated [1166]. In this vein, as galectin-3/CD45 interaction modulates apoptosis resistance in DLBCL, removal of cell-surface galectin-3 from CD45 with GCS-100 rendered DLBCL cells susceptible to chemotherapeutic agents [1167].

Galectin-3 role in metastasis

Circulating levels of galectin-3 are significantly higher in cancer patients, especially those with metastasis [1168]. Metastasis (the development of secondary tumors in a part of the body that is far from the original primary cancer) constitutes the primary cause of death for >90% of patients with cancer [1169,1170,1171]. Despite that metastasis is usually linked to epithelial cancers (known as carcinomas), all cancers (including hematologic malignancies) have the capacity to metastasize [1172]. Numerous studies have indicated that galectin-3 is involved in multiple stages of cancer progression and metastasis and may render anticancer activities in several ways [1173,1174]:

1. The intracellular galectin-3 is anti-apoptotic (providing survival advantage to cancer cells).
2. Galectin-3 promotes tumor neoangiogenesis.
3. The extracellular galectin-3 is involved in homotypic aggregation.
4. Tumor–endothelial cell interactions required for metastasis are mediated by endothelium-associated galectin-3 and cancer cell-associated TF antigen.
5. Tumor cell secreted galectin-3 induces apoptosis of cancer-infiltrating T-cells to promote immune escape and tumor progression.

The metastatic cascade

The metastatic cascade can be broadly separated into three main processes: invasion, intravasation and extravasation. The metastatic cascade is dependent on the loss of adhesion between cells, which initiates the process of invasion, the first step of metastasis. Mechanistically, the loss of cell-cell adhesion capacity allows malignant tumor cells to dissociate from the primary tumor mass and changes in cell-matrix interaction enable the cells to invade the surrounding stroma [1175]. The blood vessel within the tumor's vicinity can then provide a route for the detached cells to enter the circulatory system and metastasize to distant sites; the process of intravasation [1176,1177]. Extravasation constitutes a multistep phenomenon that can be divided into different phases. The extravasation process is initialized by rolling, relatively low-affinity binding, of leukocytes mediated by the selectin family of adhesion molecules. Interestingly, tumor cells exploit these mechanisms used by leukocytes to roll, arrest and adhere to the vascular endothelium [1178,1179]. In this vein, compelling evidence indicates that selectins regulate adhesion of circulating cancer cells to the walls of blood vessels. In particular, the presence of E-selectin ligands on cancer cells correlates with enhanced adhesion to the activated endothelium [1180,1181,1182,1183]. Moreover, during selectin-mediated rolling, integrins are activated, and then bind to their endothelial ligands to mediate a tight adhesion (or arrest) of the leukocytes. Noteworthily, integrins are a family of heterodimeric membrane glycoproteins composed of noncovalently associated α and β subunits that mediate cell-matrix and cell-cell interactions [1184,1185]. After adhesion, N-cadherin (also known as CDH2) mediates the final steps of extravasation (transmigrate tumor cells through the vascular endothelium by a procedure named diapedesis) [1186]. Intriguingly, tumor cells imitate leukocyte mechanisms for extravasation [1187]. However, the adhesion molecules and ligands involved in tumor cell extravasation are somehow different from leukocytes suggesting additionally or alternatively non-leukocyte-like mechanisms [1188]. For instance, tumor cells do not express selectins, but their respective ligands. Moreover, being the main adhesion molecules of leukocytes, the expression of several integrins, especially of the β2 subgroup, is restricted to leukocytes. In contrast to integrins, galectins are a group of adhesion receptors that leukocytes share with tumor cells. In this vein, overwhelming evidence shows that galectins are involved in extravasation [1189]. In this vein, galectin-3 expression in cancer cells was associated with a metastatic phenotype in several experimental systems [1190]. As the main link between a cell and the ECM, integrins have an essential role in the invasion process, mainly through their interactions with various ECM molecules such as collagens, laminins, fibronectin and tenascin [1191]. Mechanistically, integrin-mediated adhesion of fibronectin triggers a negative feedback signal that blocks the formation of E-cadherin mediated cell-to-cell adhesion [1192]. Dissolving E-cadherin-dependent junctions by integrin-mediated adhesion leads to separation of unparted cancer cells or groups of cancer cells from adjacent normal cells and the basement membrane below which drives the transition from carcinoma in situ to invasive cancer [1193]. In addition, the interaction between integrins and ECM enhances cell adhesion and activates cancer cell pro-survival and anti-apoptotic programs, resulting in the development of drug resistance [1194]. In a similar vein, integrin-dependent adhesion mediates leukemia cell interactions with their microenvironment. Strikingly, integrin-mediated drug resistance has been reported in T-ALL, CLL and AML [1195]. In AML, the integrin-binding glycoprotein CD98 plays a central role in chemoresistance by driving engagement of leukemia cells with their microenvironment and maintaining LSCs. Not surprisingly, Bajaj et al., suggested that CD98 inhibition should be considered for targeting both adult and pediatric leukemia [1196]. Noteworthily, glycosylation affects the functions of integrins [1197,1198,1199]. To explain further, integrins exist in a continuum of conformations between bent-closed non-ligand-bound (also termed inactive) and extended-open ligand-bound (also termed active) states [1200]. N-glycosylation positions were suggested to affect the equilibrium between these two conformers [1201]. Interestingly, galectin-3 oligomers clamp the bent-closed state to prime it for endocytic uptake, retrograde trafficking to the Golgi apparatus, and subsequent polarized secretion to the leading edge of migrating cells to enter a new functional cycle [1202]. This cycle is important for integrin-mediated functions, including cell adhesion and persistent cell migration [1203].

The role of galectin-3 in modulating integrins/ECM glycoproteins

GnT-5/MGAT5 modification of N-glycans on integrins and other adhesion receptors influence membrane remodeling and ECM assembly [1204,1205,1206,1207,1208,1209]. It was shown that the α6β4-integrin (β4-integrin), a receptor for laminin-332 and an essential component of the hemidesmosome (an anchoring structure in the basal membrane of stratified epithelial cells), is a major carrier of N-glycans and is associated with poor prognosis, tumorigenesis, and metastasis. Binding of galectin-3 to β4-integrin via β1,6GlcNAc-branched N-glycans promoted β4- integrin–mediated cell motility and invasion [1210]. Moreover, overexpression of MGAT5 leads to a substantial increase in cell migration mediated by α3β1 integrin on the laminin 5 substrate [1211]. In addition, galectin-3 interactions with GnT-5/MGAT5- modified N-glycans at the cell surface of mammary carcinoma cells stimulate α5β1-integrin activation, enhancing fibronectin fibrillogenesis and fibronectin-dependent tumor cell spreading, and motility [1212]. Galectin-3 was also shown to interact directly with ECM glycoproteins such as fibronectin, collagen IV, elastin, laminin, and hensin [1213]. Intriguingly, the integrin-binding glycoprotein CD98 is a galectin-3 ligand implicated in integrin-mediated adhesion of human cancer cell lines [1214]. Furthermore, galectin-3 binding to N-cadherin contributes to destabilization of cell–cell junctions by enhancing turnover of N-cadherin and other glycoconjugates, which might favor cell migration process [1215]. It is worth noting that the upregulation of N-cadherin (mainly exists in nerve tissue, muscle and fibroblasts) followed by the downregulation of E-cadherin (mainly exists in epithelial tissue) is the hallmark of EMT [1216]. This “cadherin switch” increases the ability of tumor cells to invade and metastasize to distant sites, which predicts poor prognosis. Therefore, EMT is considered a process in which tumor cells transform from a nonmotile epithelial phenotype to a migratory mesenchymal phenotype [1217].

The TF-MUC1-galectin-3 axis role in metastasis

Increased expression of the TF antigen has a big impact on promoting cancer progression and metastasis. To reiterate, the TF antigen, present in the core I structure of MUC1, is generally masked by sialic acid in normal cells but is exposed or nonsialylated in malignant and premalignant epithelia [1218,1219]. Interestingly, a striking difference was observed between interactions of galectin-1 and -3 toward the TF disaccharide (Galβ1,3GalNAc) found in O-glycans [1220,1221]. Galectin-3 was found to interact with TF antigen with 100-fold higher affinity compared to galectin-1 [1222]. Not surprisingly, substantial evidence indicated that the cancer-associated TF antigen promotes metastasis through binding to galectin-3 [1223]. Following the escape from primary tumor and intravasation, the first task that blood-borne neoplastic cells encounter is to survive the cell-detachment-induced apoptosis or anoikis (a type of programmed cell death that results from the loss of anchorage and detachment from ECM, which disrupts integrin ligation) and a journey through the circulation. Intriguingly, galectin-3 has been shown to overcome anoikis—a barrier to tumor metastasis—through the galectin-3-MUC1 interaction. Mechanistically, the interaction between galectin-3 and MUC1 (a natural ligand of galectin-3 that is overexpressed in cancer), via binding of galectin-3 to the oncofetal TF antigen on MUC1 [1224], breaks the “protective shield” of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 [1225] and E-selectin ligands (MUC1 carry sLeA and sLeX epitopes that act as ligands for selectins) [1226]. This leads to increased cancer cell homotypic aggregation [1227] and cancer cell heterotypic cell adhesion to vascular endothelium [1228], two important steps in metastasis. Therefore, inhibition of MUC1/TF antigen-galectin- 3 interactions may be a potential strategy to reduce tumor progression and metastasis. Like epithelial tumors, cancer specific MUC1 glycoforms are over-expressed on MM cells [1229]. Consequently, the TF-MUC1-galectin-3 axis (Figure-3) constitutes a novel therapeutic target in MM. Moreover, MUC1 cell surface polarization increases MUC1–EGFR association leading to increased and prolonged EGFR activation and signaling. These mechanisms might contribute to EGFR-associated tumorigenesis and cancer progression and could also influence the effectiveness of blocking the action of EGFR in patients undergoing cancer therapy [1230]. In this context, galectin-3 lattice itself was found to reduce EGFR lateral mobility and internalization, and to increase EGFR signaling [1231]. Additionally, MUC1 stimulates tumor cell release from initial tumor sites that promote metastasis [1232,1233,1234]. Furthermore, galectin-3 protects cancer cells from various forms of apoptosis via mainly suppressing mitochondrial apoptosis pathways [1235,1236,1237]. In addition to galectin-3-MUC1 interaction, galectin-3 protects cancer cells from anoikis by regulating their transition through the cell cycle, i.e., by inducing a cell cycle arrest at an anoikis-insensitive point (late G1 phase) [1238]. Moreover, galectin-3 anti-apoptotic effect modulates cancer cell sensitivity to various chemotherapeutic agents, many of which are used in hematologic malignancies such as etoposide [1239], doxorubicin [1240], dexamethasone, and bortezomib [1241]. In addition to its anti-apoptotic functions, galectin-3 also has pro-apoptotic roles [1242]. Elevated galectin-3 levels have been shown to be prognostic for poor survival in many cancers including leukemia, lymphomas, breast cancer, and thyroid cancer. On the other hand, decreased levels of galectin-3 appear to be detrimental to patients with CLL or prostate cancer [1243,1244,1245,1246]. A possible explanation for this variance is that the localization of galectin-3 is essential to its function. In fact, the function of galectin-3 will vary depending on whether it is in the nucleus, cytoplasm, or secreted into the extracellular spaces or in the circulation [1247]. It has been demonstrated that galectin-3 is predominantly located in the cytoplasm; and in contrast to nuclear galectin-3, cytoplasmic galectin-3 is usually associated with an aggressive phenotype in cancer cells [1248].

Figure 3: The TF-MUC1-galectin-3 axis in multiple myeloma.
The increased expression of the galectin-3-ligand TF antigen by cancer-associated MUC1, and the increased concentration of circulating galectin-3, all of which are common features in multiple myeloma (MM), promotes metastasis by induction of MUC1 polarization, exposing smaller adhesion molecules on the cell surface, including CD44, and E-selectin ligands, which increases tumor cell aggregation and favors the formation of tumor micro-emboli, preventing anoikis initiation and enhancing circulating tumor cell survival.

Galectin-9

Human galectin-9 is a 36-kDa protein that contains 135 amino acids and is encoded by the LGALS9 gene [1249]. Galectin-9 was identified from murine embryonic kidney and human Hodgkin’s lymphoma tissues in 1997 [1250,1251]. Galectin-9 typically binds internal LacNAc units, with a preference for linear poly-LacNAc glycans [1252]. Strikingly, Gcnt2, which catalyzes I-branch (blood group I antigen) formation on glycan ligands of galectin-9 (poly- LacNAcs) attenuates galectin-9 binding [1253]. Galectin-9 can form multivalent lattices due to the different oligosaccharide-binding affinities of its two CRDs [1254]. Interestingly, its long peptide linker allows the CRDs to have rotational freedom, enhancing multimerization and lattice formation [1255]. Galectin-9 has attracted much attention because of its multiple biological functions and strong immunomodulatory effects in tumor metastasis [1256]. Not surprisingly, galectin-9 has emerged as a biomarker and therapeutic target in cancer [1257,1258]. Intriguingly, galectin-9 has conflicting roles in cancer biology, the so-called double-edged sword role [1259]. For instance, the expression of galectin-9 has been linked to tumor cell adhesion and metastasis which correlated with unfavorable prognosis in several cancers such as brain tumor [1260], pancreatic cancer [1261,1262], and AML [1263]. Recently, Hung et al., demonstrated the potential efficacy of human galectin-9 neutralizing mAbs in protecting T-cells from galectin-9-induced cell death and promoting the killing of cancer cells by T-cells in vitro, which provides a rationale for targeting galectin-9 in cancer immunotherapy [1264]. On the other hand, galectin-9 can induce apoptosis and inhibit tumor growth of HCC [1265]. Hence, galectin-9 was proposed as a new prognostic factor with antimetastatic potential in patients with HCC [1266]. In addition, galectin-9 has also been reported to suppress tumor cell migration and metastasis in another study using highly metastatic melanoma and colon cancer cells [1267]. Overall, the loss of galectin-9 expression in many solid cancers is closely associated with metastatic progression, and treatment with recombinant galectin-9 prevents metastatic spread in various preclinical cancer models [1268]. In contrast to galectin-1 and -3, galectin-9 does not bind to glycans on CD43 or CD45 on T-cells [1269]. Surprisingly, however, galectin-9 is much more potent than galectin-1 in inducing T-cell death. It is worth mentioning that TIM-3 and CD44 have been identified as glycoprotein receptors for galectin-9 [1270]. Since CD44 is the galectin-9 receptor on neutrophils, galectin-9 was identified as a soluble mediator of neutrophil activation with pro-adhesive effects observed in cancer as well as autoimmune/ inflammatory diseases [1271]. Whereas CD44 is also not required for T-cell susceptibility to galectin-9, TIM-3, expressed on T helper 1 (Th1) CD4 T-cells, was identified as an essential receptor for galectin-9-induced death of Th1 cells in vitro and in vivo [1272]. In this context, galectin-9/TIM-3 interaction is considered a major immune checkpoint pathway that can be exploited for targeting in immunotherapies [1273]. In this vein, TIM-3 and its ligand galectin-9 constitute an autocrine loop which drives the self-renewal of AML stem cells by activating the NF-κB and β-catenin pathways [1274]. Besides, human AML cells possess a secretory pathway through which TIM-3 participates in galectin-9 secretion and is also released in a free soluble form [1275]. While AML patients have a higher expression of TIM-3 on their T-cells, TIM-3 is used as an important surface marker for exhausted and dysfunctional T-cells associated with disease progression [1276,1277]. Galectin-9 also impairs NK cell cytotoxicity through association with TIM-3 in AML [1278,1279]. To sum up, the galectin-9–TIM-3 pathway helps AML cells escape host immune attack by impairing the immunological activities of cytotoxic T-cells as well as NK cells [1280,1281,1282,1283]. In a similar vein, Choukrani et al., showed that recombinant galectin-9 treatment induced caspase-independent cell death in Ara-C-sensitive as well as Ara-C-resistant AML cell lines and primary patient-derived AML cells, including CD34+ AML stem cells; however, treatment excluded the healthy cord blood-derived CD34+ stem cells. Intriguingly, galectin-9 was shown to potentiate the cytotoxic effect of Azacytidine in patients who are not eligible for intensive Ara-C treatment [1284]. Recently, recombinant galectin-9 has shown promising therapeutic activity in preclinical models of various hematological malignancies, including ATLL [1285], T-cell leukemia [1286], MM [1287], CML [1288], as well as Burkitt and Hodgkin lymphoma cells [1289]. In MM, galectin-9 also showed significant therapeutic activity toward primary patient-derived myeloma cells, even in tumors resistant to conventional therapeutics [1290]. Intriguingly, treatment with recombinant galectin-9 reduced the severity of GvHD in both T-cell-deplete and T-cell-replete transplanted mice [1291]. Strikingly, the main mechanism of galectin-9-mediated immunoregulation involves the galectin-9-TIM-3 axis in T-cells. However, Myeloid- Derived Suppressor Cell (MDSC) accumulation in transgenic mice with persistently high galectin-9 expression was observed in a model of lung inflammation, indicating that a potential immunosuppressive mechanism distinct from the galectin-9- TIM-3 axis might exist [1292]. Noteworthily, TIM-3, by itself, is a bona fide target for the treatment of myeloid malignancies. Targeting TIM-3 - metaphorically - kills two birds with one stone by balancing the immune system and eliminating LSCs (the principal cause of patient relapse) in AML [1293]. MBG453, or Sabatolimab™, is an anti-TIM-3 mAb that interferes with the galectin-9-TIM-3 interaction and has been demonstrated to elicit immune-boosting, anti-leukemic activity [1294]. Clinical trials are currently underway to evaluate the safety and efficacy of MBG453 combination therapy in patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS) or AML and who are not fit for intensive chemotherapy [1295]. As TIM-3 is not expressed on normal hematopoietic stem cells [1296], targeting TIM-3 with sabatolimab holds promise as a therapeutic strategy for patients with AML [1297,1298].

I-type lectins (Siglecs)

Siglecs are I-type lectins highly expressed on innate and adaptive immune cells including human macrophages, T-cells, B-cells, DCs, and NK cells. The Siglecs family includes the conserved Siglecs (Siglec-1, Siglec-2, Siglec-4, and Siglec-15) and the rapidly evolving CD33rSiglecs, including Siglec-3 (CD33), Siglec-5, Siglec-6, Siglec-7, Siglec-8, Siglec-9, Siglec-10, Siglec-11, Siglec-14, and Siglec-16. Ligands for Siglec receptors (Sialoglycans) are broadly expressed in a variety of human tumors and in a diversity of common cancer cell lines [1299]. Most human Siglec receptors are inhibitory in nature (excluding Siglec-11, Siglec-14, Siglec-15, Siglec-1 and Siglec-4). Inhibitory Siglecs contain ITIM and ITIM-like motifs within their intracellular domain (the cytoplasmic tail). Upon binding to complementary sialoglycans in their local milieu, engagement results in down-regulation of the immune responses, particularly innate immune responses to cancer cells, that ultimately lead to cancer progression. Mechanistically, sialoglycan-Siglec interactions have been demonstrated to contribute to an immunosuppressive TME through the induction of a pro-tumorigenic phenotype in TAMs, inhibition of NK cell and neutrophil activation, reduced DC maturation and antigen presentation, and damped T-cell responses. Strikingly, inhibitory Siglecs can thereby inhibit immune cell activation similar to PD-1 after engagement by PDL1 [1300]. Therefore, the sialoglycan–Siglec axis is considered a novel glyco-immune checkpoint in cancer [1301,1302]. In particular, the CD33-related Siglec-7 and Siglec-9 on NK cells are of particular interest in the context of tumor immunotherapy owing to their critical roles in tumor cell immunoevasion. Analogous to classical checkpoint receptor PD-1, Siglec-7 binds the mucin CD43 on leukemia cell surfaces and delivers an immune inhibitory signal, similar to galectins -1 and -3 [1303]. It is widely known that NK cells - a class of innate lymphoid cells - are the primary defenders against cancer precursors. Mechanistically, NK cells play a crucial role in early recognition and elimination of transformed cells that lose MHC-I expression (“missing-self recognition”) or express danger ligands (“induced-self recognition”) through the production of pro-inflammatory cytokines, such as IFNγ and tumor necrosis factor (TNF), and by their specialized cytolytic functions [1304,1305]. NK cells, just like CD8+ T-cells, are key players in all three phases of cancer immunoediting [1306]. Recent evidence suggests that cancer-associated sialoglycans expressed by several human cancers inhibit anti-tumor immune activation by engaging Siglec-7 and Siglec-9 on NK cells [1307,1308]. Mechanistically, NK cell-mediated killing of tumor cells can be blocked in a dose-dependent manner by the interactions between tumor sialoglycans and Siglec-7 and Siglec-9 on human NK cells. Moreover, the expression of Siglec-7 and Siglec-9 on TAMs enhances cancer progression by driving macrophage polarization toward the tumor-promoting M2 phenotype [1309,1310,1311,1312,1313]. Itziar Ibarlucea-Benitez et al., showed that Siglec-7/9 blockade can significantly reduce tumor burden in vivo by prevention of macrophage polarization into TAM phenotype and thus reprogramming of the immunesuppressive TME [1314]. Ligands for inhibitory Siglec-7/-9 on NK cells are increased in melanoma, HCC, pancreatic cancer, colon adenocarcinoma, cervical cancer, breast cancer, NSCLC, head and neck cancer as well as hematological malignancies [1315]. There is compelling experimental and clinical evidence for the hypersialylation, often attributed to sialyltransferase upregulation leading to enhanced expression of sialoglycans in tumors, to correlate with poor prognosis and reduced survival owing to increased metastatic potential. In addition, hypersialylation plays a cytoprotective role and contributes to chemotherapy and radiotherapy resistance in several cancers. Intriguingly, the available evidence implicates hypersialylation in cellular trafficking, drug resistance and resistance to immune therapies, through modulation of the TME, in MM. In addition to the many reported sialyltransferases highly expressed in MM, O’Dwyer et al., also observed elevated levels of expression of ST3GAL4 that were associated with inferior PFS and OS in MM cells [1316]. In this vein, a landmark paper by Daly et al., provided evidence that the Siglec/Siglec ligand axis is hijacked by MM cells [1317]. Strikingly, it was shown for the first time that hypersialylation is implicated in facilitating evasion of NK cell-mediated immunosurveillance in MM through interactions of Siglec-7 with sialylated PSGL-1 (also called SELPLG), being the predominant Siglec-7 ligand on MM cells. Conversely, by using both a sialidase and sialyltransferase inhibitor, desialylation strongly enhanced NK cell–mediated cytotoxicity against MM cells. Interestingly, desialylation can uncover CD38 expression, a well-validated target in MM, and maximize NK cell-mediated ADCC in the presence of daratumumab (an anti-CD38 moAb) as well as disrupt the inhibitory Siglec-7–Siglec-7L (PSGL-1) axis, enhancing clearance of MM cells by NK cells. As PSGL-1 is highly expressed in MM biopsies as well as on MM cell lines where it regulates the homing and adhesion of MM cells to the microenvironment [1318,1319], PSGL-1 should be envisaged as a potential therapeutic target for cancer immunotherapy in MM. In addition, the glycoprotein CD43 also acts as a ligand for Siglec-7 in MM as well as leukemia (e.g., CML [1320]) and lymphoma cell lines, and blocking its interaction with Siglec-7 sensitizes malignant cells to immune cell lysis [1321]. It is important to note that the glycan epitope (glycotope) recognized by Siglec-7 is the disialyl core 1 O-glycan tetrasaccharide (disialyl-T) expressed predominantly on CD43, CD45, and PSGL-1 counter receptors. In this context, CD43 protein is a primary determinant of Siglec-7 ligand expression on cancer cell lines. Although CD43 is expressed in all types of immune cells (except for resting B-cells), Siglec-7 binds selectively to CD43disialyl-T but not to other CD43 glycoforms expressed in the immune system [1322]. Therefore, targeting Siglec-7–PSGL-1 and CD43–Siglec-7 checkpoints may be potential targets for cancer therapy. Apart from Siglec-7 ligands (CD43 and PSGL-1), overexpression of the mucin genes MUC1 and MUC21 conferred resistance to NK cells in MM lines. In contrast, the glycosylation regulator signal peptide peptidase-like 3 (SPPL3) deletion facilitates NK cell evasion. SPPL3 encodes an intramembrane protease that cleaves transmembrane glycosyltransferases such as GnT-5/MGAT5 (that catalyze the formation of highly branched N-glycans and LacNAc extensions that prevent NK-mediated killing) in the Golgi apparatus [1323]. Recently, Zhuang et al., performed SPPL3 knockout in several patient-derived DLBCL cell lines (RIVA, OCI-LY1, and WSUFSCCL) and observed a consistent increase in resistance to NK-mediated killing upon SPPL3 deletion in these cell lines. Mechanistically, the SPPL3 knockout resulted in MGAT5 being retained inside SPPL3-deficient cells, leading to an increase of complex N-glycans, including higher-mass glycans carrying longer poly-LacNAc extensions, which points to a shared NK evasion mechanism arising from SPPL3 deletion and the modification of cellular glycosylation status in malignant B-cells. Interestingly, they also found that B3GNT2 deletion reduced LacNAc addition and restored SPPL3-knockout cell sensitivity to NK cells. These shreds of evidence suggest that high N-glycan branching contributes to the resistant phenotype [1324]. In this context, B3GNT2 encodes the main glycosyltransferase that extends highly branched N-glycans by transfer of GlcNAc moiety in a β1,3 linkage with a terminal unsialylated galactose, preferentially on the GnT-5/MGAT5-generated β-1,6-linked branch in tri- and tetra-antennary N-glycans [1325]. Noteworthily, B3GNT2 ranks as one of the highly amplified genes in DLBCL patients, suggesting a potential alteration in glycosylation and immune evasion [1326]. Collectively, the glycosylation regulator SPPL3, heavily glycosylated mucins, and the recently identified Siglec-7 ligands CD43 and PSGL-1 provide further evidence that glycosylation plays a crucial role in regulating NK cell–cancer interactions with potential opportunities for therapeutic targeting to enhance NK cell immunotherapy [1327]. Currently, different methods targeting the sialoglycan–Siglec axis have already been successfully tested in early clinical trials, among them antibodies are already in clinical development [1328]. Moreover, among the 15 Siglecs found in mammals, Siglec-2 (CD22) and Siglec-3 (CD33) have already been proven to be potent targets for immunotherapy. Siglec-2 is primarily expressed on the surface of mature B-cells, where it targets the binding of α2,6-linked sialic acid-containing ligands. The presence of ligands on N-glycans is responsible for inhibiting galectin-1 binding. This interaction is crucial for the BCR signaling on the cell membrane, followed by binding with antigen [1329]. Not surprisingly, Siglec-2 has emerged as an attractive therapeutic target in B-cell malignancies [1330,1331,1332]. After the initial development in R/R aggressive B-cell NHL, inotuzumab ozogamicin (InO), an ADC consisting of a CD22-targeting immunoglobulin G4 humanized mAb conjugated to the cytotoxic antibiotic calicheamicin, moved to CD22+ R/R B-ALL [1333]. Noteworthily, the cell surface glycoprotein CD22 is expressed in >90% of B-ALL patients. Strikingly, InO demonstrated significant activity in R/R B-ALL in both adult and pediatric trials as either a single agent or in combination chemotherapy regimens, which led to its FDA approval for the treatment of R/R B-ALL in pediatric and adult patients [1334]. Contextually, InO showed a significantly higher remission rate compared with standard intensive chemotherapy in adults with R/R B-cell ALL in the phase 3 INO-VATE ALL trial [1335]. The post hoc subgroup analysis of the INO-VATE trial confirmed that InO remains efficacious and has a similar safety profile for R/R B-ALL in patients with a high disease burden, defined herein as bone marrow blast (BMB) >90% [1336]. The robust remission rate in the high disease burden subgroup of INO-VATE contrasts with another targeted treatment, blinatumomab, where remission rates were lower in patients with ≥50% BMB vs. <50% BMB (29 vs. 73%) [1337]. Similarly, patients with higher BMB% (≥5% vs. <5%) treated with CAR T-cell therapy experienced poorer outcomes (remission rate 75 vs. 95%, median OS 12.4 vs. 20.1 months) [1338]. In addition, new research is attempting to expand the potential applications of InO in B-ALL, including using it in combination with chemotherapy and/or other immunotherapies, in the frontline treatment of ALL, and in treatment of measurable residual disease (MRD). Strikingly, the greatest potential of InO lies in combination therapy either in the frontline or salvage settings. Interestingly, very encouraging outcomes have been observed with InO in newly diagnosed B-ALL, whether combined with chemotherapy, blinatumomab, or both [1339]. In this vein, Jabbour et al., recently showed that InO was safe and effective in eradicating MRD in patients with B-ALL in CR (the MRD conversion rate was 69%, which translated into a 2-year relapse-free survival (RFS) of 54% and a 2-year OS of 60%) [1340]. Furthermore, a phase I clinical trial (NCT03233854) tested bispecific CAR T-cells targeting CD19/CD22 (CD19-22.BB.z-CAR) in adults with R/R B-ALL and LBCL, which demonstrated safety and impressive clinical activity in B-ALL. CD19-22.BB.z- CAR T-cells were clinically active in both B-ALL, with 82% achieving an MRD− CR, and in LBCL with an objective response rate (ORR) of 62%. However, the lymphoma arm was closed in this study as the 6-month PFS in LBCL (29%, 95% CI 12–48%) was similar to tisagenlecleucel/Kymriah® (a CD19-directed CAR T-cell therapy), but enrollment is still ongoing in patients with B-ALL. Interestingly, this work provided evidence that antigen−/lo escape is a major pathway of resistance after CD19-CAR T-cell therapy for LBCL, and quantitative antigen density in LBCL correlates with outcomes after CAR T-cell therapy [1341]. In a similar vein, Joshua and colleagues developed a novel BiTE consisting of humanized anti-CD22 and anti-CD3 single chain variable fragments, demonstrating that CD22 can be utilized as an alternate target antigen to CD19 or CD20 in a BiTE formulation for B-cell malignancies. The CD22-BiTE showed tumor growth inhibition, comparable to blinatumomab, in an established B-ALL xenograft mouse model. Interestingly, the combination of blinatumomab and CD22-BiTE yielded increased efficacy in vivo when compared to the single agents, suggesting that this novel construct could be used as a primary, combination, or post-CD19 directed therapy [1342]. On the other hand, Siglec-3 (a myeloid cell marker) has been considered as a therapeutic target for AML [1343,1344]. In a way similar to InO, gemtuzumab ozogamicin (GO) is another ADC targeting CD33-expressing leukemic cells (>80% in patients with AML) that substantially improved outcomes in patients with AML [1345,1346,1347]. Noteworthily, the cytotoxic effects of both GO and InO are inversely proportional to the amount of P-gp, which indicates that P-gp contributes to their clinical resistance [1348,1349,1350]. As mentioned earlier, the MDR phenotype correlates with expression of P-gp.

Therapeutic implications

It needs to be emphasized that as a hallmark of cancer, aberrant glycosylation is not just a consequence, but also a driver of a malignant phenotype. In a similar vein, aberrant glycosylation allows for the rational design of biomarker discovery research [1351]. In addition to biomarker discovery by glycomics or glycoproteomics, glycan-related vaccines, antibody therapy, or carbohydrate recognition molecules, namely, glycan-based therapeutics or glycomimetics, are promising strategies for the future. Strikingly, the specific glycan structures found on tumor cells, known as the tumor glyco-code, can alter how the immune system perceives cancer cells and can induce immune suppression [1352]. Not surprisingly, novel therapies targeting tumor-associated glycans and their biosynthesis are currently being investigated in several clinical trials [1353]. Importantly, interference with glycan–lectin interactions that are able to skew the immune system function represent a new immune checkpoint and a potential new target for cancer immunotherapy. Noteworthily, tumor cells utilize these interactions to either evade immune cell detection or inhibit the anti-tumor immune response [1354].

In this context, some of the therapeutic applications of glycobiology-targeted therapies in hematologic malignancies are outlined here:

1. Removal of 9-O-acetyl residues from Neu5Ac on the cell surface by an O-acetylesterase made ALL cells more vulnerable to vincristine and nilotinib, suggesting that Neu5Ac de-O-acetylation could be used as therapy to eradicate drug-resistant ALL cells [1355].
2. Absence or therapeutic blockade of the E-selectin receptor using small molecule mimetic GMI-1271/Uproleselan effectively inhibits niche-mediated pro-survival signaling and dampens AML blast regeneration [1356]. In addition, supporting evidence showed that combination treatment with uproleselan reduced MM resistance to carfilzomib and lenalidomide, as well as AML to cytarabine, and enhanced their therapeutic effects as demonstrated by reduced tumor growth and prolonged mice survival [1357].
3. Galectin-9 has an antiproliferative effect on MM cell lines and patient-derived myeloma cells by inhibiting the JNK and p38 MAPK signaling pathways. Therefore, galectin-9 can be used as a new therapeutic option to treat MM [1358].
4. Two labs, one run by sugar chemist and recent Nobel Prize winner Carolyn Bertozzi, PhD, and another headed by cancer expert Dean Felsher, MD, PhD, discovered that the proto-oncogene MYC controls expression of the sialyltransferase ST6GALNAC4, which is necessary to make a glycan known as disialyl-T that appears in abundance on the surface of MYC-driven cancer cells. Disialyl-T functions as a “don’t eat me” signal by engaging Siglec-7, thereby inhibiting anticancer immune responses. The combined high expression of MYC and ST6GALNAC4 identifies patients with high-risk cancers with reduced tumor myeloid infiltration. Patients with high MYC expression including DLBCL [1359], CLL [1360], BL [1361], and T-ALL [1362] may be particularly responsive to inhibition of ST6GALNAC4 activity either directly or indirectly by therapeutically targeting its product disialyl-T with an antibody or degradation with an antibody-sialidase conjugate [1363,1364]. Interestingly, MYC was found to be translocated in 36% of patients with MM [1365], which could hold opportunities for therapeutic intervention in MM [1366].
5. The Gb3-binding lectin-CARs have demonstrated target-specific cytotoxicity against Burkitt's lymphoma-derived cell lines as well as solid tumor cells from colorectal and triple-negative breast cancer [1367]. Noteworthily, Gb3 is highly expressed by B-cells found within GCs (GC B-cells), where it is essential for the production of high-affinity antibodies [1368].
6. Significantly slower tumor progression was observed in the CD19 BiTE-sialidase treated group compared to the CD19 BiTE treated group, demonstrating better in vivo anti-tumor effects of the sialidase fusion protein [1369].
7. PSGL-1 is a potential therapeutic target for MM. Immunotherapy with anti-PSGL-1 mAbs induced in vivo killing of MM cells (provided that complement regulatory proteins are neutralized) through apoptosis, ADCC, and complement-dependent cytotoxicity (CDC) [1370].
8. Glinsky and Raz have advocated for development of MCP, a galectin-3 antagonist that acts by inhibiting galectin-3 antiapoptotic effects [1371]. Consistent with the previous myeloma study [1372], GCS-100 (an MCP) was able to suppress both ERK phosphorylation and MCL-1 expression in AML cells. GCS-100 has proved effective in pre-clinical models of MM, lymphoma, AML, as well as solid tumors [1373,1374,1375,1376]. Considering that galectin-3 is a major regulator of Bcl-2 function, the Raz laboratory has also advocated combining anti-Bcl-2 treatment (e.g., BH3 mimetics) with therapy targeting galectin-3 (e.g., GCS-100) to improve the efficacy of anti-Bcl-2 treatment in several hematologic malignancies [1377].
9. Aasted et al., generated 4C8, a cancer-specific mAb, against tumor-associated Tn-glycosylated CD44v6. 4C8 CAR T-cells were effective against T-cell leukemia and several solid cell lines while sparing healthy keratinocytes [1378].
10. Tang et al., found that AML patients with FLT3/ITD or DNMT3A mutations had higher expression of CD44v6, in contrast to normal specimens. CD44v6 CAR T-cells eliminated CD44v6+ AML cells, especially AML cells with FLT3 or DNMT3A mutations, while demonstrating potent anti-leukemic efficacy and safety both in vitro and in vivo [1379].
11. Vaxevanis et al., suggested for the first time the proteoglycan biglycan (BGN) as a novel prognostic biomarker and therapeutic target of sAML/MDS by its direct inhibition through BGN-specific antibodies and/or inflammasome inhibitors [1380].
12. A phase I/IIa clinical trial has been performed to study safety, efficacy, and feasibility of CD44v6 CAR T-cell immunotherapy in AML and MM patients, mediating potent anti-tumor effects against primary AML and MM while sparing normal hematopoietic stem cells and CD44v6-expressing keratinocytes [1381]. In addition, CD44v6-targeting nanomedicine has been explored as a promising tool for cancer therapy. This targeted nanoparticle development represents a launching point for future improvements and therapeutic and/or diagnostic opportunities [1382].
13. J. Bae et al., demonstrated increased LAG-3 expression on proliferating CD3+ T-cells in MM patient Bone Marrow Mononuclear Cells (BMMCs) and peripheral blood mononuclear cells (PBMCs), as well as robust surface and intracellular expression of its ligand, galectin-3, in CD138+ patient MM cells and MM cell lines. LAG-3/galectin-3 blockade (through LAG-3 and/or galectin-3 inhibition) can efficiently enhance the proliferation of T-cells in MM patients and functional activities of MM-specific CTL, including XBP1/CD138/CS1-targeting memory CD8+ T-cells, against MM. These results identify LAG-3/galectin-3 as an alternative mechanism of immune resistance and provide the rationale for targeting LAG-3/galectin-3, alone or in combination with immunotherapeutic approaches, to improve patient outcome in MM [1383].
14. Layal El Halabi et al., found that LAG-3 and TIM-3 are nearly always expressed in the TME of classical Hodgkin lymphoma (cHL). TIM-3 was detected at the surface of a third of Hodgkin/Reed-Sternberg (HRS) cells [1384]. Several preclinical cancer models showed that combining anti-PD-1 with anti-LAG-3 or anti-TIM-3 appeared to be synergistic [1385,1386,1387,1388,1389,1390,1391,1392] and may also help overcome resistance [1393]. This provides a rationale for targeting LAG-3 and/or TIM-3 in combination with anti-PD-1 antibodies in the treatment of R/R HL. Currently, a phase 3 randomized clinical trial (NCT05508867) aims to assess the safety and tolerability as well as compare efficacy of coformulated favezelimab, MK-4280 (a humanized IgG4 LAG-3 inhibitor that inhibits the binding of LAG-3 to MHC class II) plus pembrolizumab, MK-3475 (a PD-1 inhibitor), with physician's choice chemotherapy of bendamustine or gemcitabine in patients with PD-(L)1-refractory, R/R cHL. Furthermore, a phase 1/phase 2 clinical trial (NCT03598608) aims to evaluate the safety and efficacy of favezelimab in combination with pembrolizumab using a non-randomized study design in patients with several hematological malignancies (cHL, DLBCL, and indolent NHL). Results of the analysis focusing on anti-PD-1-naïve patients with R/R cHL revealed that the combination of favezelimab and pembrolizumab was associated with an ORR of 73% (22/30 patients), including 23% Complete Response (CR) at a median follow-up of 13.5 months. The median PFS was 19 months, and the median OS was not reached. The 12-month OS rate was 96% [1394,1395]. This efficacy was also shown in the cohort of patients with R/R classical HL who failed an anti-PD-1 treatment, suggesting the combination may reinduce a response in these patients. The ORR was 31% (9/29) including 7% CR after a median follow-up of 16.5 months. The median PFS and OS were 9 months and 26 months, respectively [1396].
15. Corcoran et al., showed that genetic, pharmacological, and enzymatic approaches that remove sialic acid from N-linked glycans on CD79B lead to enhanced tumor killing by Polatuzumab Vedotin (Pola-V), an ADC directed to the CD79B subunit of the BCR, in DLBCL cell lines [1397]. Mechanistically, glycosylated residues on CD79A and CD79B create a glycan shield around the Pola-V binding site which precludes binding to its target. Therefore, these findings reveal the striking impact of epitope glycosylation, specifically a2,6 sialylation, on the binding of Pola-V to CD79B and thereby its ability to kill tumor cells, and also unravel the molecular basis of heterogeneity in response to Pola-V [1398].
16. Pang et al., demonstrated that targeting galectin‐9 may hold potential value for the treatment of acute GvHD (aGvHD) after haplo‐HSCT. Mechanistically, exogenous galectin‐9 was found to mitigate aGvHD by restoring the Treg/Teffs (effector T-cells) balance and suppressing the PI3K/AKT/mTOR pathway. The increased Treg cells can inhibit the activation of Th1 and Th17 cells by secreting TGF‐β, thus alleviating aGvHD and inducing immune tolerance [1399].
17. Interesting new research uncovered a proinflammatory stem cell niche driving myelofibrosis, through a galectin-1 signaling axis. This discovery points to galectin-1 as a promising therapeutic target with disease-modifying effects (altering the inflammatory niche and reducing fibrosis) in MPNs [1400].
18. As discussed earlier, ST3GAL4 has been suggested to synthesize ligands for E-selectin, an adhesion receptor that facilitates the survival of AML stem cells within the BM niche. Interestingly, V. Krishnamoorthy et al., recently found that upregulation of ST3GAL4 in AML facilitates immune evasion by increasing the biosynthesis of ligands for the inhibitory Siglec-9. Integrated CRISPR genomic screening and clinical bioinformatic analysis identified ST3GAL4 as a potential driver of Siglec-9 ligand expression in AML. Depletion of ST3GAL4 by CRISPR-Cas9 knockout dramatically reduced the expression of Siglec-9 ligands in AML cells. Mass spectrometry analysis of cell-surface glycosylation in ST3GAL4 knockout cells revealed that Siglec-9 primarily binds N-linked sialoglycans on these cell types. In addition, this study found that ST3GAL4 knockout enhanced the sensitivity of AML cells to phagocytosis by Siglec-9-expressing macrophages. Intriguingly, this work confirms that ST3GAL4 is strongly implicated in AML pathogenesis and implies that the ST3GAL4 enzyme itself may actually be the most impactful target for the development of therapeutic inhibitors in AML [1401].
19. Intriguingly, the galectin-9–TIM-3 axis is upregulated in B-ALL, negatively correlating with clinical outcome, and galectin-9 impairs CD19-CAR T-cell function. Falgàs et al., showed that blocking the galectin-9–TIM-3 axis in B-ALL enhances the persistence and efficacy of CD19-CAR T-cells in vivo and ex vivo [1402]. Mechanistically, TIM-3 is commonly expressed on CAR T-cells in the context of “exhaustion,” and binding of TIM-3 to galectin-9 can lead to reduced T-cell function and apoptosis [1403].
20. Substantial evidence suggests that BMSCs contribute to the progression of myeloid malignancies by remodeling the TME [1404,1405]. In this context, Feng et al., observed a significantly higher proportion of M2 TAMs in the BMSCs of MDS/AML compared to healthy donors. This phenomenon is associated with the aberrantly glycosylated levels in leukemic stromal cells, highlighting a promising target for MDS/AML immunotherapy. Mechanistically, downregulated bisecting GlcNAc levels in BMSCs of MDS/AML patients drove TAMs polarization towards the M2 phenotype through the secretion of TGF-β1, which elevated PD-L1 expression and thereby impaired CD8+ T-cell function, facilitating immune escape and the progression of MDS/AML [1406].

Challenges and Future Directions in Immunotherapy: Unlocking New Horizons in Cancer Immunotherapy

Although immunotherapy has shown promising activities in several solid tumors, its effects remain suboptimal in patients with liquid tumors. For instance, despite advancements in the treatment landscape of MM, such as incorporation of the anti- CD38 mAb daratumumab, most of the patients inevitably experience relapse [1407]. In addition, the current immunotherapy platforms have already been riddled with issues concerning mainly their safety profile and affordability since their inception. For instance, Kymriah® costs $475,000 per patient in the US, which is unaffordable for an ordinary family [1408]. Not surprisingly, the high demand and expensive costs associated with CAR T-cell therapy might prove unsustainable for health systems [1409]. Hence, an effective drug at an affordable price is an unmet need [1410]. On 28 November 2023, the FDA released a statement that the agency is investigating reports of T-cell malignancies, including CAR-positive lymphoma, in patients who received treatment with BCMA- or CD19-directed autologous CAR T-cell immunotherapies [1411,1412,1413]. Due to the seriousness of this risk, ongoing monitoring and longitudinal surveillance remain a clinical standard in the post-CAR setting [1414]. Within this context, Elsallab et al., provided additional information on the numbers of second malignancies reported after CAR-T therapies. They found that second primary malignancies were reported in 4.3% (536 of 12394) adverse events after CAR-T therapies in the Food and Drug Administration Adverse Event Reporting System (FAERS). Strikingly, myeloid and T-cell neoplasms were disproportionately more frequent, with 208 reports of myelodysplasia and 106 reports of acute myeloid leukemias, which warrants further follow-up [1415]. Strikingly, relapse remains the major obstacle of CAR T-cell therapy leaving many hematologic malignancies inevitably fatal, and therefore new treatment strategies are imperative. Clinical evidence indicates that a large proportion of patients with B-cell malignancies suffer from relapse after CAR T-cell therapy [1416]. The initial impressive results of CAR T-cell therapy were coupled with the occurrence of relapse in approximately 30%-50% of patients after having achieved a CR [1417]. Consequently, understanding the mechanics of poor response or relapse is critical in advancing CAR T-cell therapy [1418]. Possible reasons include CAR T-cell intrinsic qualities such as expansion capacity and T-cell exhaustion/dysfunction cell state, in addition to CAR T-cell extrinsic factors such as antigen escape and immune suppression by the hostile BM microenvironment [1419,1420]. As T-cell dysfunction is now well established as a cause of CAR T-cell failure [1421], replacing T-cells by NK cells is expected to gain substantial momentum as an alternative therapeutic approach. Interestingly, patients infused with CAR-NK cells did not represent significant adverse events, such as CRS [1422]. However, just like CAR T-cell therapy, patients treated with CAR NK-cells also developed progressive disease despite showing initial encouraging responses [1423,1424]. In both cases, considerable effort is still needed to replicate the success observed with CAR cell therapies in B-lymphoid malignancies in other malignancies [1425]. Furthermore, the therapeutic potential of deeper understanding of co-inhibitory B7-CD28 pathways led to the FDA approval of several ICIs for cancer immunotherapy [1426].

However, despite the marked clinical success of ICB in the treatment of several tumors, many patients do not respond, relapse, or are deemed no longer eligible for further ICB treatment [1427]. Given the dire outcomes for patients with hematologic malignancies, seeking alternative therapeutics options is a genuine demand rather than a fantasy. In this context, multiple lines of evidence suggest that TACAs are: (1) more tumor specific than protein targets; (2) expressed on tumor cell surface; (3) highly abundant; and (4) significant in tumor biology, i.e., suppressing and evading immune surveillance in the TME, altering oncogenic signaling pathways, promoting tumor survival, progression, and metastasis [1428]. In fact, glycobiology has already produced many effective drugs with validated results against several solid tumors. In parallel to solid tumors, the field of glycobiology is already replete with a host of important prognostic biomarkers and therapeutic targets for liquid tumors. Overwhelming evidence supports the huge impact of glycosylation changes in hematologic malignancies; and as such, aberrant glycosylation provides an attractive resource for immunotherapy.

In particular, the repertoire of cancer-associated glycans known as TACAs expressed on liquid tumors is highly versatile and constitute a great opportunity to avail from targeted approaches. Noteworthily, glycan targeting may offer major advantages in relation to protein targeting [1429]. Since they are barely expressed on normal tissues, TACAs are truly tumor-specific antigens which indicates that targeting them offers less ‘off-target’ or ‘on-target off-tumor’ toxicities [1430]. Within this context, in addition to the known approaches (e.g., CAR T-cell therapy), TACAs can also be targeted by novel methods including lectins, lectibodies [1431,1432], and glycan-specific nanobodies [1433,1434]. Notably, significant advancements have been made in understanding plant and microbial lectins as therapeutic agents against various viral diseases in recent years. Among them, mannose-specific lectins have been proven as promising anti-viral agents against a variety of viruses [1435]. In this vein, I have personally proposed therapeutic lectins as a new modality of immunotherapy that can avail of the CDC-driven TACA-targeted killing of cancer cells [1436]. Supporting this hypothesis, rVAR2 represents a proof-of-principle model promoting the use of lectins against hematologic malignancies. rVAR2 is a recombinant VAR2CSA, a lectin from P. falciparum that detects an oncofetal CS structure found on many proteoglycans including syndecan-1, CD44 and Chondroitin Sulfate Proteoglycan 4 (CSPG4) that are present in a high proportion of malignant cell lines including MM and B-ALL [1437,1438]. Interestingly, CSPG4 is an established treatment target for KMT2A-R B-ALL [1439]. CS structure on CSPG4 is just one example of many immune targets that are heavily glycosylated glycoproteins in which their glycotopes can be added to the pool of TACAs. Noteworthily, neither the genome, transcriptome nor the proteome can individually predict the structural nature, distribution and dynamics of glycan chains in proteins. However, glycoproteomics attempts to bridge this gap by addressing the glycome as it appears in the proteome [1440]. Therefore, it is imperative to investigate the glycoproteomics of surface glycoproteins (e.g., CD44 variant isoforms) in order to characterize its altered glycosylation profiles and identify targetable TACAs for novel immunotherapy. In addition, glycoproteomic analysis has emerged as a promising tool for biomarker discovery and development in early detection of cancers and prediction of treatment efficacy including response to immunotherapies [1441]. Indeed, glycosylation of glycoproteins is crucial for their response to immunotherapy. Examples include CD38 in MM [1442,1443] and CD19 in B-ALL [1444], in which glycosylation changes enable resistance to daratumumab and CAR T-cells respectively. Furthermore, it has been repeatedly demonstrated that the interactions between lectins and altered/ tumor-specific cell surface carbohydrates ‘turns on’ an immunosuppressive milieu, also known as the tumor glyco-code, which is a prominent mechanism by which tumors escape anti-tumor immune responses [1445]. Unsurprisingly, glycan-lectin interactions have uncovered an array of novel signaling pathways that mimic the known immune checkpoints CTLA-4 and PD-1 [1446]. As a matter of fact, Siglecs are mostly inhibitory receptors similar to known immune checkpoints including PD-1 or CTLA- 4 that are successfully targeted with blocking antibodies for cancer immunotherapy [1447]. Consequently, disrupting these immunosuppressive glyco-immune checkpoints could serve as a blueprint to develop novel or improved cancer immunotherapeutic modalities, including T-cell therapies. In particular, the sialoglycan- Siglec, TF-MUC1-galectin-3 and galectin-9–TIM-3 axes are promising targets for checkpoint inhibitor–type intervention in hematologic malignancies. Signaling pathways that govern these pathways must also be understood to fully harness their full potential. Interestingly, these glyco-immune checkpoints can be combined with ICBs to improve their efficacy [1448]. For instance, recent evidence suggested that targeted tumor desialylation in the TME enhances tumor control by converting immunologically inert tumors into inflamed ones [1449] as well as synergizes with ICB [1450]. One of the strategies designed to desialylate the TME was through antibody conjugation to a sialidase which has shown to improve the anti-tumor immune response [1451]. In a similar vein, very recent work shows that sialic-acid removal is synergistic with BiTE treatment in vitro [1452]. In a similar vein, the E-selectin/sLeX axis has been reported to regulate both hematopoietic stem and leukemic cell proliferative dynamics. As such, targeting E-selectin receptor/ sLeX signaling pathways holds great potential to develop effective anti-cancer regimens in the treatment of liquid tumors [1453]. In addition, the tumor glyco-code can be seen as neoantigens that represent interesting targets for therapeutic and diagnostic approaches [1454]. Intriguingly, since glycan modifications are dictated by the repertoire of glycosyltransferases and substrates responsible for their synthesis [1455], the field of glycobiology unveiled several metabolic vulnerability loops and glycosyltransferases with druggable and therapeutic potential.

Conclusion

Despite that immunotherapy has shown great potential in cancer treatment, a significant proportion of patients experience disease recurrence or resistance, owing to primary or acquired drug resistance driven by tumor immune escape. Hence, developing new strategies to overcome immune escape is the only way to enhance the response efficiency of immunotherapy. Within this context, compelling evidence suggests that aberrant glycosylation contributes to the formation of a complex “glyco- code” on the surface of tumor cells implicated in suppressing anti-tumor immune responses, which plays a crucial role in tumor development and progression. Not surprisingly, aberrant glycosylation has emerged as a promising target for immunotherapy, ushering in a new frontier in cancer treatment: glyco-immunology. By decoding the intricate interplay between glycosylation and immunosuppression, this field holds the potential to revolutionize cancer therapeutics. Indeed, the key insights into the glycobiological landscapes of hematologic malignancies presented in this article should provide the impetus for devising novel strategies aimed at eradicating the malignant clone as well as galvanize hematologists/oncologists to design and conduct robust clinical trials in this field. To this end, future editions of the major hematology/oncology textbooks including “The Bethesda Handbook of Clinical Hematology”, “Rodak's Hematology”, “Wintrobe's Clinical Hematology Book”, “Nathan and Oski's Hematology of Infancy and Childhood”, “Williams Manual of Hematology”, and “Lanzkowsky's Manual of Pediatric Hematology and Oncology” must integrate background information on ‘Glycobiology in Hematology’.As a concluding remark, this article serves to lay the foundation for future revolution of therapeutics in hematologic oncology in the context of recent advances in glycobiological research.

References

1. Anker J, Pal SK, Kim-Schulze S, Wang H, Halperin R, Uzilov A, et al. Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer. J Immunother Cancer. 2023;11(8).

   [Crossref] [Google Scholar] [PubMed]

2. Coley WB. Contribution to the knowledge of sarcoma. Ann Surg. 1891;14:199-220.

   [Crossref] [Google Scholar] [PubMed]

3. Kerr WG, Chisholm JD. The next generation of immunotherapy for cancer: Small molecules could make big waves. J Immunol. 2019;202(1):11-19.

   [Crossref] [Google Scholar] [PubMed]

4. Zaidi N, Jaffee EM. Immunotherapy transforms cancer treatment. J Clin Invest. 2019;129(1):46-47.

   [Crossref] [Google Scholar] [PubMed]

5. Allen C, Zeidan AM, Bewersdorf JP. BiTEs, DARTS, BiKEs and TriKEs-are antibody based therapies changing the future treatment of AML? Life. 2021;11(6):465.

   [Crossref] [Google Scholar] [PubMed]

6. Couzin-Frankel J. Cancer immunotherapy. Science. 2013;1432-1433

   [Crossref] [Google Scholar] [PubMed]

7. Gravitz L. Cancer immunotherapy. Nature. 2013;504(7480).

   [Crossref] [Google Scholar] [PubMed]

8. Spencer KR, Wang J, Silk AW, Ganesan S, Kaufman HL, Mehnert JM. Biomarkers for immunotherapy: Current developments and challenges. Am Soc Clin Oncol Educ Book. 2016; 35:493-503.

   [Crossref] [Google Scholar] [PubMed]

9. Green M, Feng FY, Mehra R, Spratt DE, Green M, Feng FY, et al. Convergence of immunotherapy, radiotherapy and prostate cancer: Challenges and opportunities. Immunotherapy. 2017;9(9):695-699.

   [Crossref] [Google Scholar] [PubMed]

10. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371(16):1507-1517.

    [Crossref] [Google Scholar] [PubMed]

11. Pérez RE, Melero I, Kopecka J, Sarmento-Ribeiro AB, García AM, De Las Rivas J. Cancer immunotherapy resistance based on immune checkpoints inhibitors: Targets, biomarkers, and remedies. Drug Resist Updat. 2020;53:100718.

    [Crossref] [Google Scholar] [PubMed]

12. Sharma P, Hu Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell. 2017;168(4):707-723.

    [Crossref] [Google Scholar] [PubMed]

13. Senthebane DA, Rowe A, Thomford NE, Shipanga H, Munro D, Al Mazeedi MA, et al. The role of tumor microenvironment in chemoresistance: To survive, keep your enemies closer. Int J Mol Sci. 2017;18(7):1586.

    [Crossref] [Google Scholar] [PubMed]

14. Khalaf K, Hana D, Chou JT, Singh C, Mackiewicz A, Kaczmarek M. Aspects of the tumor microenvironment involved in immune resistance and drug resistance. Front Immunol. 2021;12:656364.

    [Crossref] [Google Scholar] [PubMed]

15. Rad HS, Monkman J, Warkiani ME, Ladwa R, O'Byrne K, Rezaei N, et al. Understanding the tumor microenvironment for effective immunotherapy. Med Res Rev. 2021;41(3):1474-1498.

    [Crossref] [Google Scholar] [PubMed]

16. Decock J, Comito G, Zaravinos A. Tumor microenvironment, inflammation, and resistance to immunotherapies. Front Oncol. 2023;13:1215332.

    [Crossref] [Google Scholar] [PubMed]

17. Yin X, He L, Guo Z. T‐cell exhaustion in CAR‐T‐cell therapy and strategies to overcome it. Immunology. 2023;169(4):400-411.

    [Crossref] [Google Scholar] [PubMed]

18. Gumber D, Wang LD. Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion. EBioMedicine. 2022;77.

    [Crossref] [Google Scholar] [PubMed]

19. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: From immunosurveillance to tumor escape. Nat Immunol. 2002;3(11):991-998.

    [Crossref] [Google Scholar] [PubMed]

20. Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348(6230):74-80.

    [Crossref] [Google Scholar] [PubMed]

21. Grosser R, Cherkassky L, Chintala N, Adusumilli PS. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer cell. 2019;36(5):471-482.

    [Crossref] [Google Scholar] [PubMed]

22. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol. 2013;13(4):227-242.

    [Crossref] [Google Scholar] [PubMed]

23. Aggarwal V, Workman CJ, Vignali DA. LAG-3 as the third checkpoint inhibitor. Nat Immunol. 2023;24(9):1415-1422.

    [Crossref] [Google Scholar] [PubMed]

24. Bardhan K, Anagnostou T, Boussiotis VA. The PD1: PD-L1/2 pathway from discovery to clinical implementation. Front Immunol. 2016;7:550.

    [Crossref] [Google Scholar] [PubMed]

25. Vandenborre K, Van-Gool SW, Kasran A, Ceuppens JL, Boogaerts MA, Vandenberghe P. Interaction of CTLA‐4 (CD152) with CD80 or CD86 inhibits human T‐cell activation. Immunology. 1999;98(3):413-421.

    [Crossref] [Google Scholar] [PubMed]

26. Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell. 2007;129(1):123-134.

    [Crossref] [Google Scholar] [PubMed]

27. Lipkowitz MS, Leal-Pinto E, Cohen BE, Abramson RG. Galectin 9 is the sugar-regulated urate transporter/channel UAT. Glycoconj J. 2002;19:491-498.

    [Crossref] [Google Scholar] [PubMed]

28. Graydon CG, Mohideen S, Fowke KR. LAG3's enigmatic mechanism of action. Front Immunol. 2021;11:615317.

    [Crossref] [Google Scholar] [PubMed]

29. Ge Z, Peppelenbosch MP, Sprengers D, Kwekkeboom J. TIGIT, the next step towards successful combination immune checkpoint therapy in cancer. Front Immunol. 2021;12:699895.

    [Crossref] [Google Scholar] [PubMed]

30. Boles KS, Vermi W, Facchetti F, Fuchs A, Wilson TJ, Diacovo TG, et al. A novel molecular interaction for the adhesion of follicular CD4 T cells to follicular DC. Eur J Immunol. 2009;39(3):695-703.

    [Crossref] [Google Scholar] [PubMed]

31. Wu L, Mao L, Liu JF, Chen L, Yu GT, Yang LL, et al. Blockade of TIGIT/CD155 signaling reverses T-cell exhaustion and enhances antitumor capability in head and neck squamous cell carcinoma. Cancer Immunol Res. 2019;7(10):1700-1713.

    [Crossref] [Google Scholar] [PubMed]

32. Levin SD, Taft DW, Brandt CS, Bucher C, Howard ED, Chadwick EM, et al. Vstm3 is a member of the CD28 family and an important modulator of T‐cell function. Eur J Immunol. 2011;41(4):902-915.

    [Crossref] [Google Scholar] [PubMed]

33. Khan M, Arooj S, Wang H. Soluble B7-CD28 family inhibitory immune checkpoint proteins and anti-cancer immunotherapy. Front Immunol. 2021;12:651634.

    [Crossref] [Google Scholar] [PubMed]

34. Schildberg FA, Klein SR, Freeman GJ, Sharpe AH, Schildberg FA, Klein SR, et al. Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity. 2016;44(5):955-972.

    [Crossref] [Google Scholar] [PubMed]

35. Andrews LP, Marciscano AE, Drake CG, Vignali DA. LAG 3 (CD 223) as a cancer immunotherapy target. Immunol Rev. 2017;276(1):80-96.

    [Crossref] [Google Scholar] [PubMed]

36. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 2015;6(6):1792.

    [Crossref] [Google Scholar] [PubMed]

37. Chakraborty A, Dimitroff CJ. Cancer immunotherapy needs to learn how to stick to its guns. J Clin Invest. 2019;129(12):5089-5091.

    [Crossref] [Google Scholar] [PubMed]

38. Ganesh K, Stadler ZK, Cercek A, Mendelsohn RB, Shia J, Segal NH, et al. Immunotherapy in colorectal cancer: Rationale, challenges and potential. Nat Rev Gastroenterol Hepatol. 2019;16(6):361-375.

    [Crossref] [Google Scholar] [PubMed]

39. Tawfik EA, Aldrak NA, Albrahim SH, Alzahrani DA, Alfassam HA, Alkoblan SM, et al. Immunotherapy in hematological malignancies: Recent advances and open questions. Immunotherapy. 2021;13(14):1215-1229.

    [Crossref] [Google Scholar] [PubMed]

40. Kennedy LB, Salama AK. A review of cancer immunotherapy toxicity. CA: A cancer journal for clinicians. 2020;70(2):86-104.

    [Crossref] [Google Scholar] [PubMed]

41. Wang DY, Johnson DB, Davis EJ. Toxicities associated with PD-1/PD-L1 blockade. Cancer J. 2018;24(1):36-40.

    [Crossref] [Google Scholar] [PubMed].

42. Chan A, Torelli S, Cheng E, Batchelder R, Waliany S, Neal J, et al. Immunotherapy-associated atherosclerosis: A comprehensive review of recent findings and implications for future research. Curr Treat Options Cardiovasc Med. 2023;25(12):715-735.

    [Crossref] [Google Scholar] [PubMed]

43. Sterner RC, Sterner RM. Immune effector cell associated neurotoxicity syndrome in chimeric antigen receptor-T cell therapy. Front Immunol. 2022;13:879608.

    [Crossref] [Google Scholar] [PubMed]

44. Rebechi MT, Bork JT, Riedel DJ. HHV-6 encephalitis after chimeric antigen receptor T-cell therapy (CAR-T): 2 case reports and a brief review of the literature. Open Forum Infect Dis. 2021; 8(11):470.

    [Crossref] [Google Scholar] [PubMed]

45. Spanjaart AM, van der Valk FM, van Rooijen G, Brouwer MC, Kersten MJ. Confused about confusion. N Engl J Med. 2022;386(1):80-87.

    [Crossref] [Google Scholar] [PubMed]

46. Lareau CA, Yin Y, Maurer K, Sandor KD, Daniel B, Yagnik G, et al. Latent human herpesvirus 6 is reactivated in CAR T cells. Nature. 2023;623(7987):608-615.

    [Crossref] [Google Scholar] [PubMed]

47. Davis JA, Sborov DW, Wesson W, Julian K, Abdallah AO, McGuirk JP, et al. Efficacy and safety of CD34+ stem cell boost for delayed hematopoietic recovery after BCMA directed CAR T-cell therapy. Transplant Cell Ther. 2023;29(9):567-571.

    [Crossref] [Google Scholar] [PubMed]

48. Cordeiro A, Bezerra ED, Hirayama AV, Hill JA, Wu QV, Voutsinas J, et al. Late events after treatment with CD19-targeted chimeric antigen receptor modified T cells. Biology of Blood and Marrow Transplantation. 2020;26(1):26-33.

    [Crossref] [Google Scholar] [PubMed]

49. Wang L, Hong R, Zhou L, Ni F, Zhang M, Zhao H, et al. New-onset severe cytopenia after CAR-T cell therapy: Analysis of 76 patients with relapsed or refractory acute lymphoblastic leukemia. Front Oncol. 2021;11:702644.

    [Crossref] [Google Scholar] [PubMed]

50. Doan A, Mueller KP, Chen A, Rouin GT, Daniel B, Lattin J, et al. FOXO1 is a master regulator of CAR T memory programming. Res Sq. 2023.

    [Crossref] [Google Scholar] [PubMed]

51. Byrne M, Oluwole OO, Savani B, Majhail NS, Hill BT, Locke FL. Understanding and managing large B cell lymphoma relapses after chimeric antigen receptor T cell therapy. Biol Blood Marrow Transplant. 2019;25(11):344-351.

    [Crossref] [Google Scholar] [PubMed]

52. Zhang X, Zhu L, Zhang H, Chen S, Xiao Y. CAR-T cell therapy in hematological malignancies: Current opportunities and challenges. Front Immunol. 2022; 13:927153.

    [Crossref] [Google Scholar] [PubMed]

53. Wu Z, Cheung NV. T cell engaging bispecific antibody (T-BsAb): From technology to therapeutics. Pharmacol Ther. 2018;182:161-175.

    [Crossref] [Google Scholar] [PubMed]

54. Tian Z, Liu M, Zhang Y, Wang X. Bispecific T cell engagers: An emerging therapy for management of hematologic malignancies. J Hematol Oncol. 2021 ;14(1):75.

    [Crossref] [Google Scholar] [PubMed]

55. Bailey SR, Berger TR, Graham C, Larson RC, Maus MV. Four challenges to CAR T cells breaking the glass ceiling. Eur J Immunol. 2023;53(11):2250039.

    [Crossref] [Google Scholar] [PubMed]

56. Gagelmann N, Sureda A, Montoto S, Murray J, Bolaños N, Kenyon M, et al. Access to and affordability of CAR T-cell therapy in multiple myeloma: an EBMT position paper. Lancet Haematol. 2022;9(10):786-795.

    [Crossref] [Google Scholar] [PubMed]

57. Hefazi M, Litzow MR. Recent advances in the biology and treatment of B-cell acute lymphoblastic leukemia. Blood Lymphat Cancer. 2018:47-61.

    [Crossref] [Google Scholar] [PubMed]

58. Hochberg J, El-Mallawany NK, Cairo MS. Humoral and cellular immunotherapy in ALL in children, adolescents, and young adults. Clin Lymphoma Myeloma Leuk. 2014;14:6-13.

    [Crossref] [Google Scholar] [PubMed]

59. Willasch AM, Salzmann ME, Krenn T, Duerken M, Faber J, Opper J, et al. Treatment of relapse after allogeneic stem cell transplantation in children and adolescents with ALL: The frankfurt experience. Bone Marrow Transplant. 2017;52(2):201-208.

    [Crossref] [Google Scholar] [PubMed]

60. Ravi P, Kumar SK, Cerhan JR, Maurer MJ, Dingli D, Ansell SM, et al. Defining cure in multiple myeloma: A comparative study of outcomes of young individuals with myeloma and curable hematologic malignancies. Blood Cancer J. 2018;8(3):26.

    [Crossref] [Google Scholar] [PubMed]

61. Lin Y, Qiu L, Usmani S, Joo CW, Costa L, Derman B, et al. Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T-cell therapy in clinical practice for relapsed and refractory multiple  myeloma: A report from the International Myeloma Working Group Immunotherapy Committee. Lancet Oncol. 2024.

    [Crossref] [Google Scholar] [PubMed]

62. Rejeski K, Jain MD, Smith EL. Mechanisms of resistance and treatment of relapse after CAR T-cell therapy for large B-cell lymphoma and multiple myeloma. Transplant Cell Ther. 2023;29(7):418-428.

    [Crossref] [Google Scholar] [PubMed]

63. Negishi S, Girsch JH, Siegler EL, Bezerra ED, Miyao K, Sakemura RL. Treatment strategies for relapse after CAR T-cell therapy in B cell lymphoma. Front Pediatr. 2024;11:1305657.

    [Crossref] [Google Scholar] [PubMed]

64.  Xu X, Sun Q, Liang X, Chen Z, Zhang X, Zhou X, et al. Mechanisms of relapse after CD19 CAR T-cell therapy for acute lymphoblastic leukemia and its prevention and treatment strategies. Front Immunol. 2019; 10:2664.

    [Crossref] [Google Scholar] [PubMed]

65. Liu Z, Lei W, Wang H, Liu X, Fu R. Challenges and strategies associated with CAR-T cell therapy in blood malignancies. Exp Hematol Oncol. 2024;13(1):22.

    [Crossref] [Google Scholar] [PubMed]

66. Bhagwat AS, Torres L, Shestova O, Shestov M, Mellors PW, Fisher HR, et al. Cytokine-mediated CAR T therapy resistance in AML. Nat Med. 2024:1-2.

    [Crossref] [Google Scholar] [PubMed

67. Fleischer LC, Spencer HT, Raikar SS. Targeting T cell malignancies using CAR-based immunotherapy: Challenges and potential solutions. J Hematol Oncol. 2019; 12:1-21.

    [Crossref] [Google Scholar] [PubMed]

68. Safarzadeh Kozani P, Safarzadeh Kozani P, Rahbarizadeh F. CAR-T cell therapy in T-cell malignancies: Is success a low-hanging fruit? Stem Cell Res Ther. 2021;12(1):527.

    [Crossref] [Google Scholar] [PubMed]

69. Nogami A, Sasaki K. Therapeutic advances in immunotherapies for hematological malignancies. Int J Mol Sci. 2022;23(19):11526.

    [Crossref] [Google Scholar] [PubMed]

70. Dong S, Ghobrial IM. Immunotherapy for hematological malignancies. J Life Sci. 2019;1(1):46.

    [Google Scholar] [PubMed]

71. Daniel Kelly Benjamin JR, Miller WC, Bayliff S, Martel L, Alexander KA, Martin PL. Infections diagnosed in the first year after pediatric stem cell transplantation. Pediatr Infect Dis J. 2002;21(3):227-234.

    [Crossref] [Google Scholar] [PubMed]

72. Pereira MR, Pouch SM, Scully B. Infections in allogeneic stem cell transplantation. Princ Pract Transplant Infect Dis. 2019:209-226.

    [Google Scholar]

73. Gratwohl A, Stern M, Brand R, Apperley J, Baldomero H, de Witte T, et al. Risk score for outcome after allogeneic hematopoietic stem cell transplantation: A retrospective analysis. Cancer. 2009;115(20):4715-4726.

    [Crossref] [Google Scholar] [PubMed]

74. Liquid tumors at a glance, Ashraf Abdullah Saad. 2024.
75. Schnaar RL, Gerardy-Schahn R, Hildebrandt H. Sialic acids in the brain: Gangliosides and polysialic acid in nervous system development, stability, disease, and regeneration. Physiol Rev. 2014.

    [Crossref] [Google Scholar] [PubMed]

76. Taylor M, Drickamer K, Imberty A, van Kooyk Y, Schnaar R, Etzler M, et al. Discovery and classification of glycan-binding proteins. Essent Glycobiol. 2022. 

    [Google Scholar]

77. Ohtsubo K, Marth JD. Glycosylation in cellular mechanisms of health and disease. Cell. 2006;126(5):855-867.

    [Crossref] [Google Scholar] [PubMed]

78. Bellis SL, Reis CA, Varki A, Cummings RD, Esko JD, et al. Glycosylation changes in cancer. Essent Glycobiol. 2022.
79. Munkley J, Elliott DJ. Hallmarks of glycosylation in cancer. Oncotarget. 2016;7(23):35478.

    [Crossref] [Google Scholar] [PubMed]

80. Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646-674.

    [Crossref] [Google Scholar] [PubMed]

81. Stanczak MA, Siddiqui SS, Trefny MP, Thommen DS, Boligan KF, von Gunten S, et al. Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells. J Clin Invest. 2018;128(11):4912-4923.

    [Crossref] [Google Scholar] [PubMed]

82. Läubli H, Varki A. Sialic acid-binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses. Cell Mol Life Sci. 2020;77(4):593-605.

    [Crossref] [Google Scholar] [PubMed]

83. Zhou X, Chi K, Zhang C, Liu Q, Yang G. Sialylation: A cloak for tumors to trick the immune system in the microenvironment. Biology. 2023;12(6):832.

    [Crossref] [Google Scholar] [PubMed]

84. Bärenwaldt A, Läubli H. The sialoglycan-Siglec glyco-immune checkpoint–a target for improving innate and adaptive anti-cancer immunity. Expert Opin Ther Targets. 2019;23(10):839-853.

    [Crossref] [Google Scholar] [PubMed]

85. Smith BA, Bertozzi CR. The clinical impact of glycobiology: Targeting selectins, siglecs and mammalian glycans. Nat Rev Drug Discov. 2021;20(3):217-243.

    [Crossref] [Google Scholar] [PubMed]

86. Segatori VI, Ferreira GM, Rojo S, Nogueira AC, Castillo JO, Gulino CA, et al. Mimicry of tumour-associated carbohydrates: is it a promising option for cancer treatment? Immuno. 2023;3(2):122-147. 

    [Crossref] [Google Scholar]

87. Amon R, Rosenfeld R, Perlmutter S, Grant OC, Yehuda S, Borenstein-Katz A, et al. Directed evolution of therapeutic antibodies targeting glycosylation in cancer. Cancers. 2020;12(10):2824.

    [Crossref] [Google Scholar] [PubMed]

88. Ross HJ, Hart LL, Swanson PM, Rarick MU, Figlin RA, Jacobs AD, et al. A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma. Lung Cancer. 2006; 54(1):69-77.

    [Crossref] [Google Scholar] [PubMed]

89. Tolcher AW, Sugarman S, Gelmon KA, Cohen R, Saleh M, Isaacs C, et al. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J Clin Oncol. 1999;17(2):478.

    [Crossref] [Google Scholar] [PubMed]

90. Katayose Y, Kudo T, Suzuki M, Shinoda M, Saijyo S, Sakurai N, et al. MUC1-specific targeting immunotherapy with bispecific antibodies: Inhibition of xenografted human bile duct carcinoma growth. Cancer Res. 1996; 56(18):4205-4212.

    [Google Scholar] [PubMed]

91. Kodama H, Suzuki M, Katayose Y, Shinoda M, Sakurai N, Takemura SI, et al. Specific and effective targeting cancer immunotherapy with a combination of three bispecific antibodies. Immunology Lett. 2002;81(2):99-106.

    [Crossref] [Google Scholar] [PubMed]

92. Li Y, Zhou C, Li J, Liu J, Lin L, Li L, et al. Single domain based bispecific antibody, Muc1-Bi-1, and its humanized form, Muc1-Bi-2, induce potent cancer cell killing in muc1 positive tumor cells. PLoS One. 2018;13(1):e0191024.

    [Crossref] [Google Scholar] [PubMed] 

93. Hoseini SS, Dobrenkov K, Pankov D, Xu XL, Cheung NK. Bispecific antibody does not induce T-cell death mediated by chimeric antigen receptor against disialoganglioside GD2. Oncoimmunology. 2017;6(6):e1320625.

    [Crossref] [Google Scholar] [PubMed]

94. O'Boyle KP, Zamore R, Adluri S, Cohen A, Kemeny N, Welt S, et al. Immunization of colorectal cancer patients with modified ovine submaxillary gland mucin and adjuvants induces IgM and IgG antibodies to sialylated Tn. Cancer Res. 1992;52(20):5663-5667.

    [Google Scholar] [PubMed]

95. Reinartz S, Köhler S, Schlebusch H, Krista K, Giffels P, Renke K, et al. Vaccination of patients with advanced ovarian carcinoma with the anti-idiotype ACA125: Immunological response and survival (phase Ib/II). Clin Cancer Res. 2004;10(5):1580-1587.

    [Crossref] [Google Scholar] [PubMed]

96. Ragupathi G, Livingston PO, Hood C, Gathuru J, Krown SE, Chapman PB, et al. Consistent antibody response against ganglioside GD2 induced in patients with melanoma by a GD2 lactone-keyhole limpet hemocyanin conjugate vaccine plus immunological adjuvant QS-21. Clin Cancer Res. 2003 (14):5214-5220.

    [Google Scholar] [PubMed]

97. Chapman PB, Morrisey D, Panageas KS, Williams L, Lewis JJ, Israel RJ, et al. Vaccination with a bivalent GM2 and GD2 ganglioside conjugate vaccine: A trial comparing doses of GD2-keyhole limpet hemocyanin. Clin Cancer Res. 2000;6(12):4658-4662.

    [Google Scholar] [PubMed]

98. Vázquez AM, Hernández AM, Macías A, Montero E, Gómez DE, Alonso DF, et al. Racotumomab: An anti-idiotype vaccine related to N-glycolyl-containing gangliosides–preclinical and clinical data. Front Oncol. 2012;2:150. 

    [Crossref] [Google Scholar] [PubMed]

99. Carr A, Rodríguez E, del Carmen Arango M, Camacho R, Osorio M, Gabri M, et al. Immunotherapy of advanced breast cancer with a heterophilic ganglioside (NeuGcGM3) cancer vaccine. J Clin Oncol. 2003;21(6):1015-1021.

    [Crossref] [Google Scholar] [PubMed]

100. Rosato F, Pasupuleti R, Tomisch J, Meléndez AV, Kolanovic D, Makshakova ON, et al. A bispecific, crosslinking lectibody activates cytotoxic T cells and induces cancer cell death. J Transl Med. 2022 ;20(1):578.

     [Crossref] [Google Scholar] [PubMed]

101. Oh YJ, Dent MW, Freels AR, Zhou Q, Lebrilla CB, Merchant ML, et al. Antitumor activity of a lectibody targeting cancer-associated high-mannose glycans. Mol Ther. 2022;30(4):1523-1535.

     [Crossref] [Google Scholar] [PubMed]

102. Notova S, Imberty A. Tuning specificity and topology of lectins through synthetic biology. Curr Opin Chem Biol. 2023;73:102275.

     [Crossref] [Google Scholar] [PubMed]

103. Gillmann KM, Temme JS, Marglous S, Brown CE, Gildersleeve JC. Anti-glycan monoclonal antibodies: Basic research and clinical applications. Curr Opin Chem Biol. 2023;74:102281.

     [Crossref] [PubMed]

104. Marofi F, Motavalli R, Safonov VA, Thangavelu L, Yumashev AV, Alexander M, et al. CAR T cells in solid tumors: Challenges and opportunities. Stem Cell Res Ther. 2021;12:1-6.

     [Crossref] [Google Scholar] [PubMed]

105. McPhedran SJ, Carleton GA, Lum JJ. Metabolic engineering for optimized CAR-T cell therapy. Nat Metab. 2024;6(3):396-408.

     [Crossref] [Google Scholar] [PubMed]

106. Johnston AC, Alicea GM, Lee CC, Patel PV, Hanna EA, Vaz E, et al. Engineering self-propelled tumor-infiltrating CAR T cells using synthetic velocity receptors. BioRxiv. 2024 :2023-12.

     [Crossref] [Google Scholar] [PubMed]

107. Raglow Z, McKenna MK, Bonifant CL, Wang W, di Magliano MP, Stadlmann J, et al. Targeting glycans for CAR therapy: The advent of sweet CARs. Mol Ther. 2022;30(9):2881-2890.

     [Crossref] [Google Scholar] [PubMed]

108. McKenna MK, Ozcan A, Brenner D, Watanabe N, Legendre M, Thomas DG, et al. Novel banana lectin CAR-T cells to target pancreatic tumors and tumor-associated stroma. J Immunother Cancer. 2023;11(1).

     [Crossref] [Google Scholar] [PubMed]

109. Kaczanowska S, Murty T, Alimadadi A, Contreras CF, Duault C, Subrahmanyam PB, et al. Immune determinants of CAR-T cell expansion in solid tumor patients receiving GD2 CAR-T cell therapy. Cancer Cell. 2024;42(1):35-51.

     [Crossref] [Google Scholar] [PubMed]

110. Pang X, Li H, Guan F, Li X. Multiple roles of glycans in hematological malignancies. Front Oncol. 2018;8:364.

     [Crossref] [Google Scholar] [PubMed]

111. Su H, Wang M, Pang X, Guan F, Li X, Cheng Y. When glycosylation meets blood cells: A glance of the aberrant glycosylation in hematological malignancies. Rev Physiol Biochem Pharmacol. 2021:85-117.

     [Crossref] [Google Scholar] [PubMed]

112. Vicente MM, Leite Gomes E, Pinho SS. Glycome dynamics in T and B cell development: basic immunological mechanisms and clinical applications. Trends Immunol. 2023.

     [Google Scholar]

113. Reis JSD, Santos MARDC, Mendonça DP, Nascimento SIMD, Barcelos PM, Lima RGCD, et al. Glycobiology of cancer: Sugar drives the show. Medicines. 2022;9(6):34.

     [Crossref] [Google Scholar] [PubMed]

114. Yang S, He Z, Wu T, Wang S, Dai H. Glycobiology in osteoclast differentiation and function. Bone Res. 2023;11(1):55.

     [Crossref] [Google Scholar] [PubMed]

115. Hirabayashi J, Arai R. Lectin engineering: The possible and the actual. Interface Focus. 2019;9(2):20180068.

     [Crossref] [Google Scholar] [PubMed]

116. Sanji AS, Manasa J, Gurav MJ, Batra SK, Chachadi VB. Cancer snap-shots: Biochemistry and glycopathology of O-glycans: A review. Int J Biol Macromol. 2024:129318.

     [Crossref] [Google Scholar] [PubMed]

117. Lübbers J, Rodríguez E, Kooyk YV. Modulation of immune tolerance via siglec-sialic acid interactions. Front Immunol. 2018;9:2807.

     [Crossref] [Google Scholar] [PubMed]

118. Bertozzi CR, Sasisekharan R. Glycomics. Essentials of glycobiology. 2nd edition. 2009.

     [Google Scholar] [PubMed]

119. Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al. Glycomics and glycoproteomics. Essent Glycobiol. 2017.

     [Crossref] [Google Scholar] [PubMed]

120. Heisterkamp N. Glycosylation as regulator of human B-cell leukaemias in bone marrow. Front Hematol. 2023;2:1279863.

     [Crossref] [Google Scholar]

121. Stanley P. Golgi glycosylation. Cold Spring Harb Perspect Biol. 2011;3(4):a005199.

     [Crossref] [Google Scholar] [PubMed]

122. Safferthal M, Bechtella L, Zappe A, Vos GM, Pagel K. Labeling of mucin-type o-glycans for quantification using liquid chromatography and fluorescence detection. ACS Meas Sci Au. 2024;4(2):223-230.

     [Crossref] [Google Scholar] [PubMed]

123. Stanley P. Genetics of glycosylation in mammalian development and disease. Nat Rev Genet. 2024:1-5.

     [Crossref] [Google Scholar] [PubMed]

124. Bagdonaite I, Marinova IN, Rudjord-Levann AM, Pallesen EM, King-Smith SL, Karlsson R, et al. Glycoengineered keratinocyte library reveals essential functions of specific glycans for all stages of HSV-1 infection. Nat Commun. 2023;14(1):7000.

     [Crossref] [Google Scholar] [PubMed]

125. Schjoldager KT, Narimatsu Y, Joshi HJ, Clausen H. Global view of human protein glycosylation pathways and functions. Nat Rev Mol Cell Biol. 2020;21(12):729-749.

     [Crossref] [Google Scholar] [PubMed]

126. Wandall HH, Nielsen MA, King-Smith S, de Haan N, Bagdonaite I. Global functions of o‐glycosylation: Promises and challenges in o-glycobiology. FEBS J. 2021;288(24):7183-7212.

     [Crossref] [Google Scholar] [PubMed]

127. Thomas D, Rathinavel AK, Radhakrishnan P. Altered glycosylation in cancer: A promising target for biomarkers and therapeutics. Biochim Biophys Acta Rev Cancer. 2021;1875(1):188464.

     [Crossref] [Google Scholar] [PubMed]

128. Helenius A, Aebi AM. Intracellular functions of N-linked glycans. Science.2001;291(5512):2364-2369.

     [Crossref] [Google Scholar] [PubMed]

129. Rudd PM, Elliott T, Cresswell P, Wilson IA, Dwek RA. Glycosylation and the immune system. Science. 2001;291(5512):2370-2376.

     [Crossref] [Google Scholar] [PubMed]

130. Lv W, Yu H, Han M, Tan Y, Wu M, Zhang J, et al. Analysis of tumor glycosylation characteristics and implications for immune checkpoint inhibitor’s efficacy for breast cancer. Front Immunol. 2022;13:830158.

     [Crossref] [Google Scholar] [PubMed]

131. Daniotti JL, Vilcaes AA, Demichelis VT, Ruggiero FM, Walker MR. Glycosylation of glycolipids in cancer: Basis for development of novel therapeutic approaches. Front Oncol. 2013; 3:306.

     [Crossref] [Google Scholar] [PubMed]

132. Hakomori SI. Tumor-associated carbohydrate antigens defining tumor malignancy: Basis for development of anti-cancer vaccines. Adv Exp Med Biol. 2001:369-402.

     [Crossref] [Google Scholar] [PubMed]

133. Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncog. 2013;18(1-2).

     [Crossref] [Google Scholar] [PubMed]

134. Purushothaman A, Mohajeri M, Lele TP. The role of glycans in the mechanobiology of cancer. J Biol Chem. 2023;299(3).

     [Crossref] [Google Scholar] [PubMed]

135. Berois N, Pittini A, Osinaga E. Targeting tumor glycans for cancer therapy: Successes, limitations, and perspectives. Cancers. 2022;14(3):645.

     [Crossref] [Google Scholar] [PubMed]

136. Dimitroff CJ. Galectin-binding o-glycosylations as regulators of malignancy. Cancer Res. 2015;75(16):3195-3202.

     [Crossref] [Google Scholar] [PubMed]

137. RodrÍguez E, Schetters ST, van Kooyk Y. The tumour glyco-code as a novel immune checkpoint for immunotherapy. Nat Rev Immunol. 2018;18(3):204-211.

     [Crossref] [Google Scholar] [PubMed]

138. Hakomori S. Glycosylation defining cancer malignancy: New wine in an old bottle. Proc Natl Acad Sci USA. 2002;99(16):10231-10233.

     [Crossref] [Google Scholar] [PubMed]

139. Arnold JN, Saldova R, Hamid UM, Rudd PM. Evaluation of the serum N‐linked glycome for the diagnosis of cancer and chronic inflammation. Proteomics. 2008;8(16):3284-3293.

     [Crossref] [Google Scholar] [PubMed]

140. Hakomori SI, Kannagi R. Glycosphingolipids as tumor-associated and differentiation markers. J Natl Cancer Inst. 1983;71(2):231-251.

     [Google Scholar] [PubMed]

141. Peixoto A, Fernandes E, Gaiteiro C, Lima L, Azevedo R, Soares J, et al. Hypoxia enhances the malignant nature of bladder cancer cells and concomitantly antagonizes protein o-glycosylation extension. Oncotarget. 2016;7(39):63138.

     [Crossref] [Google Scholar] [PubMed]

142. Cotton S, Azevedo R, Gaiteiro C, Ferreira D, Lima L, Peixoto A, et al. Targeted O-glycoproteomics explored increased sialylation and identified MUC16 as a poor prognosis biomarker in advanced-stage bladder tumours. Mol Oncol. 2017;11(8):895-912.

     [Crossref] [Google Scholar] [PubMed]

143. Kannagi R, Yin J, Miyazaki K, Izawa M. Current relevance of incomplete synthesis and neo-synthesis for cancer-associated alteration of carbohydrate determinants-Hakomori's concepts revisited. Biochim Biophys Acta. 2008;1780(3):525-531.

     [Crossref] [Google Scholar] [PubMed]

144. Boligan KF, Mesa C, Fernandez LE, von Gunten S. Cancer intelligence acquired (CIA): Tumor glycosylation and sialylation codes dismantling antitumor defense. Cell Molecular Life Sci. 2015; 72:1231-1248.

     [Crossref] [Google Scholar] [PubMed]

145. Narimatsu Y, Joshi HJ, Nason R, Van Coillie J, Karlsson R, Sun L, et al. An atlas of human glycosylation pathways enables display of the human glycome by gene engineered cells. Mol Cell. 2019;75(2):394-407.

     [Crossref] [Google Scholar] [PubMed]

146. Gagneux P, Panin V, Hennet T, Aebi M, Varki A. Evolution of glycan diversity. 2022.

     [Google Scholar]

147. Christiansen MN, Chik J, Lee L, Anugraham M, Abrahams JL, Packer NH. Cell surface protein glycosylation in cancer. Proteomics. 2014;14(4-5):525-546.

     [Crossref] [Google Scholar] [PubMed]

148. Pu C, Biyuan, Xu K, Zhao Y. Glycosylation and its research progress in endometrial cancer. Clin Transl Oncol. 2022;24(10):1865-1880.

     [Crossref] [Google Scholar] [PubMed]

149. Pietrobono S, Stecca B. Aberrant sialylation in cancer: Biomarker and potential target for therapeutic intervention? Cancers. 2021;13(9):2014.

     [Crossref] [Google Scholar] [PubMed]

150. Garnham R, Scott E, Livermore KE, Munkley J. ST6GAL1: A key player in cancer. Oncol Lett. 2019;18(2):983-989.

     [Crossref] [Google Scholar] [PubMed]

151. Bindeman WE, Fingleton B. Glycosylation as a regulator of site-specific metastasis. Cancer Metastasis Rev. 2022;41(1):107-129.

     [Crossref] [Google Scholar] [PubMed]

152. Bhalerao N, Chakraborty A, Marciel MP, Hwang J, Britain CM, Silva AD, et al. ST6GAL1 sialyltransferase promotes acinar to ductal metaplasia and pancreatic cancer progression. JCI Insight. 2023;8(19).

     [Crossref] [Google Scholar] [PubMed]

153. Ma H, Chen X, Mo S, Zhang Y, Mao X, Chen J, et al. Targeting N-glycosylation of 4F2hc mediated by glycosyltransferase B3GNT3 sensitizes ferroptosis of pancreatic ductal adenocarcinoma. Cell Death Differ. 2023;30(8):1988-2004.

     [Crossref] [Google Scholar] [PubMed]

154. Schwarz F, Aebi M. Mechanisms and principles of N-linked protein glycosylation. Curr Opin Struct Biol. 2011;21(5):576-582. 

     [Crossref] [Google Scholar] [PubMed]

155. Kizuka Y. Regulation of intracellular activity of N-glycan branching enzymes in mammals. J Biol Chem. 2024:107471.

     [Crossref] [Google Scholar] [PubMed]

156. Abdelbary M, Nolz JC. N-linked glycans: An underappreciated key determinant of T cell development, activation, and function. Immunometabolism. 2023;5(4): e00035.

     [Crossref] [Google Scholar] [PubMed]

157. Darby JF, Gilio AK, Piniello B, Roth C, Blagova E, Hubbard RE, et al. Substrate engagement and catalytic mechanisms of N-acetylglucosaminyltransferase V. ACS Catalysis.2020;10(15):8590-8596.

     [Google Scholar]

158. Cummings RD, Trowbridge IS, Kornfeld S. A mouse lymphoma cell line resistant to the leukoagglutinating lectin from Phaseolus vulgaris is deficient in UDP-GlcNAc: α-D-mannoside β1, 6 N-acetylglucosaminyltransferase. J Biol Chem. 1982;257(22):13421-13427.

     [Google Scholar] [PubMed]

159. Dennis JW, Laferté S, Waghorne C, Breitman ML, Kerbel RS. β1-6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science. 1987;236(4801):582-585.

     [Crossref] [Google Scholar] [PubMed]

160. Nagae M, Kizuka Y, Mihara E, Kitago Y, Hanashima S, Ito Y, et al. Structure and mechanism of cancer-associated N-acetylglucosaminyltransferase-V. Nat Commun. 2018;9(1):3380.

     [Crossref] [Google Scholar] [PubMed]

161. Dennis JW, Laferté S, Waghorne C, Breitman ML, Kerbel RS. β1-6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science. 1987;236(4801):582-585.

     [Crossref] [Google Scholar] [PubMed]

162. Taniguchi N, Kizuka Y. Glycans and cancer: Role of N-glycans in cancer biomarker, progression and metastasis, and therapeutics. Adv Cancer Res. 2015;126:11-51.

     [Crossref] [Google Scholar] [PubMed]

163. Lin Y, Lubman DM. The role of N-glycosylation in cancer. Acta Pharm Sin B. 2024;14(3):1098-1110.

     [Crossref] [Google Scholar] [PubMed]

164. Stanley P. A method to the madness of N-glycan complexity? Cell. 2007;129(1):27-29.

     [Crossref] [Google Scholar] [PubMed]

165. de-Souza Ferreira M, Ferreira ÉE, de Freitas Junior JC. Aberrant N-glycosylation in cancer: MGAT5 and β1, 6-GlcNAc branched N-glycans as critical regulators of tumor development and progression. Cell Oncol. 2023;46(3):481-501.

     [Crossref] [Google Scholar] [PubMed]

166. Yamamoto E, Ino K, Miyoshi E, Shibata K, Takahashi N, Kajiyama H, et al. Expression of N-acetylglucosaminyltransferase V in endometrial cancer correlates with poor prognosis. Br J Cancer. 2007;97(11):1538-1544.

     [Crossref] [Google Scholar] [PubMed]

167. Yamamoto H, Swoger J, Greene S, Saito T, Hurh J, Sweeley C, et al. β1, 6-N-acetylglucosamine-bearing N-glycans in human gliomas: Implications for a role in regulating invasivity. Cancer res. 2000;60(1):134-142. [Crossref]

     [Google Scholar] [PubMed]

168. Ho WL, Hsu WM, Huang MC, Kadomatsu K, Nakagawara A. Protein glycosylation in cancers and its potential therapeutic applications in neuroblastoma. J Hematol Oncol. 2016;9(1):1-6.

     [Crossref] [Google Scholar] [PubMed]

169. Murata K, Miyoshi E, Kameyama M, Ishikawa O, Kabuto T, Sasaki Y, et al. Expression of N-acetylglucosaminyltransferase V in colorectal cancer correlates with metastasis and poor prognosis. Clin Cancer Res. 2000;6(5):1772-1777.

     [Google Scholar] [PubMed]

170. Silva MC, Fernandes Â, Oliveira M, Resende C, Correia A, de-Freitas-Junior JC, et al. Glycans as immune checkpoints: Removal of branched N-glycans enhances immune recognition preventing cancer progression. Cancer Immunol Res. 2020;8(11):1407-1425.

     [Crossref] [Google Scholar] [PubMed]

171. Li D, Li Y, Wu X, Li Q, Yu J, Gen J, et al. Knockdown of Mgat5 inhibits breast cancer cell growth with activation of CD4+ T cells and macrophages. J Immunol. 2008;180(5):3158-3165.

     [Crossref] [Google Scholar] [PubMed]

172. Cheng L, Cao L, Wu Y, Xie W, Li J, Guan F, et al. Bisecting N-acetylglucosamine on EGFR inhibits malignant phenotype of breast cancer via down-regulation of EGFR/Erk signaling. Front Oncol. 2020;10:929.

     [Crossref] [Google Scholar] [PubMed]

173. Wei T, Li Y, Zhuo E, Zhu W, Meng H, Zhang J. Down-regulation of GnT-V inhibits nasopharyngeal carcinoma cell CNE-2 malignancy in vitro and in vivo. Cancer Lett. 2011;309(2):151-161.

     [Crossref] [Google Scholar] [PubMed]

174. Zhou X, Chen H, Wang Q, Zhang L, Zhao J. Knockdown of Mgat5 inhibits CD133+ human pulmonary adenocarcinoma cell growth in vitro and in vivo. Clin Invest Med. 2011;34(3):155-162.

     [Crossref] [Google Scholar] [PubMed]

175. Wei T, Liu Q, He F, Zhu W, Hu L, Guo L, et al. The role of N-acetylglucosaminyltransferases V in the malignancy of human hepatocellular carcinoma. Exp Mol Pathol. 2012;93(1):8-17.

     [Crossref] [Google Scholar] [PubMed]

176. Liu J, Liu H, Zhang W, Wu Q, Liu W, Liu Y, et al. N-acetylglucosaminyltransferase V confers hepatoma cells with resistance to anoikis through EGFR/PAK1 activation. Glycobiology. 2013;23(9):1097-109.

     [Crossref] [Google Scholar] [PubMed]

177. Li B, Su S, Zhang MY, He L, Wang QD, He K. Effect of GnT-V knockdown on the proliferation, migration and invasion of the SMMC7721/R human hepatocellular carcinoma drug-resistant cell line. Mol Med Rep. 2016;13(1):469-476.

     [Crossref] [Google Scholar] [PubMed]

178. Huang B, Sun L, Cao J, Zhang Y, Wu Q, Zhang J, et al. Downregulation of the GnT-V gene inhibits metastasis and invasion of BGC823 gastric cancer cells. Oncol Rep. 2013;29(6):2392-400.

     [Google Scholar] [PubMed]

179. Hollander EE, Flock RE, McDevitt JC, Vostrejs WP, Campbell SL, Orlen MI, et al. N-glycosylation by Mgat5 imposes a targetable constraint on immune-mediated tumor clearance. JCI Insight. 2024;9(12):e178804.

     [Crossref] [Google Scholar] [PubMed]

180. Dennis JW, Lau KS, Demetriou M, Nabi IR. Adaptive regulation at the cell surface by N‐glycosylation. Traffic. 2009;10(11):1569-1578.

     [Crossref] [Google Scholar] [PubMed]

181. Kobayashi K, Morishita A, Iwama H, Fujita K, Okura R, Fujihara S, et al. Galectin-9 suppresses cholangiocarcinoma cell proliferation by inducing apoptosis but not cell cycle arrest. Oncol Rep. 2015;34(4):1761-1770.

     [Crossref] [Google Scholar] [PubMed]

182. Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, et al. Regulation of cytokine receptors by golgi N-glycan processing and endocytosis. Science. 2004;306(5693):120-124.

     [Crossref] [Google Scholar] [PubMed]

183. Marth JD, Grewal PK. Mammalian glycosylation in immunity. Nat Rev Immunol. 2008;8(11):874-887.

     [Crossref] [Google Scholar] [PubMed]

184. Togayachi A, Kozono Y, Ishida H, Abe S, Suzuki N, Tsunoda Y, et al. Polylactosamine on glycoproteins influences basal levels of lymphocyte and macrophage activation. Proc Natl Acad Sci. 2007;104(40):15829-15834.

     [Crossref] [Google Scholar] [PubMed]

185. Chen HL, Li CF, Grigorian A, Tian W, Demetriou M. T cell receptor signaling co-regulates multiple golgi genes to enhance N-glycan branching. J Biol Chem. 2009;284(47):32454-32461.

     [Crossref] [Google Scholar] [PubMed]

186. Osuka RF, Hirata T, Nagae M, Nakano M, Shibata H, Okamoto R, et al N-acetylglucosaminyltransferase-V requires a specific noncatalytic luminal domain for its activity toward glycoprotein substrates. J Biol Chem. 2022;298(3).

     [Crossref] [Google Scholar] [PubMed]

187. Stanley P, Moremen KW, Lewis NE, Taniguchi N, Aebi M. N-glycans.2022.

     [Google Scholar]

188. Xu Q, Isaji T, Lu Y, Gu W, Kondo M, Fukuda T, et al. Roles of N-acetylglucosaminyltransferase III in epithelial-to-mesenchymal transition induced by transforming growth factor β1 (TGF-β1) in epithelial cell lines. J Biol Chem. 2012;287(20):16563-16574.

     [Crossref] [Google Scholar] [PubMed]

189. Pinho SS, Oliveira P, Cabral J, Carvalho S, Huntsman D, Gärtner F, et al. Loss and recovery of Mgat3 and GnT-III mediated E-cadherin N-glycosylation is a mechanism involved in epithelial-mesenchymal-epithelial transitions. PLoS One. 2012;7(3):e33191.

     [Crossref] [Google Scholar] [PubMed]

190. Yoshimura M, Nishikawa A, Ihara Y, Nishiura T, Nakao H, Kanayama Y, et al. High expression of udp‐n‐acetylglucosamine: β‐d mannoside β‐1, 4‐n‐acetylglucosaminyltransferase III (GnT‐III) in chronic myelogenous leukemia in blast crisis. Int J Cancer. 1995;60(4):443-449.

     [Crossref] [Google Scholar] [PubMed]

191. Yoshimura M, Ihara Y, Ohnishi A, Ijuhin N, Nishiura T, Kanakura Y, et al. Bisecting N-acetylglucosamine on K562 cells suppresses natural killer cytotoxicity and promotes spleen colonization. Cancer Res. 1996;56(2):412-418.

     [Google Scholar] [PubMed]

192. André S, Kožár T, Schuberth R, Unverzagt C, Kojima S, Gabius HJ. Substitutions in the N-glycan core as regulators of biorecognition: The case of core-fucose and bisecting GlcNAc moieties. Biochemistry. 2007;46(23):6984-6995.

     [Crossref] [Google Scholar] [PubMed]

193. Peixoto A, Relvas-Santos M, Azevedo R, Santos LL, Ferreira JA. Protein glycosylation and tumor microenvironment alterations driving cancer hallmarks. Front Oncol. 2019;9:380.

     [Crossref] [Google Scholar] [PubMed]

194. Du Z, Lovly CM. Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer. 2018;17(1):1-3.

     [Crossref] [Google Scholar] [PubMed]

195. Bangarh R, Khatana C, Kaur S, Sharma A, Kaushal A, Siwal SS, et al. Aberrant protein glycosylation: implications on diagnosis and immunotherapy. Biotechnol Adv. 2023;66:108149.

     [Crossref] [Google Scholar] [PubMed]

196. Rebbaa A, Yamamoto H, Saito T, Meuillet E, Kim P, Kersey DS, et al. Gene transfection-mediated overexpression of β1, 4-N-acetylglucosamine bisecting oligosaccharides in glioma cell line U373 MG inhibits epidermal growth factor receptor function. J Biol Chem. 1997;272(14):9275-9279.

     [Crossref] [Google Scholar] [PubMed]

197. Wu YM, Liu CH, Huang MJ, Lai HS, Lee PH, Hu RH, et al. C1GALT1 enhances proliferation of hepatocellular carcinoma cells via modulating MET glycosylation and dimerization. Cancer Res. 2013;73(17):5580-5590.

     [Crossref] [Google Scholar] [PubMed]

198. Iozzo RV, Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med. 2011;15(5):1013-1031.

     [Crossref] [Google Scholar] [PubMed]

199. Neill T, Schaefer L, Iozzo RV. Decoding the matrix: Instructive roles of proteoglycan receptors. Biochemistry. 2015;54(30):4583-4598.

     [Crossref] [Google Scholar] [PubMed]

200. Ebrahimi N, Fardi E, Ghaderi H, Palizdar S, Khorram R, Vafadar R, et al. Receptor tyrosine kinase inhibitors in cancer. Cell Mol Life Sci. 2023;80(4):104.

     [Crossref] [Google Scholar] [PubMed]

201. Saraon P, Pathmanathan S, Snider J, Lyakisheva A, Wong V, Stagljar I, et al. Receptor tyrosine kinases and cancer: Oncogenic mechanisms and therapeutic approaches. Oncogene. 2021;40(24):4079-4093.

     [Crossref] [Google Scholar] [PubMed]

202. Ghosh S, Marrocco I, Yarden Y. Roles for receptor tyrosine kinases in tumor progression and implications for cancer treatment. Adv Cancer Res. 2020;147:1-57.

     [Crossref] [Google Scholar] [PubMed]

203. Hanks SK, Quinn AM, Hunter T. The protein kinase family: Conserved features and deduced phylogeny of the catalytic domains. Science. 1988;241(4861):42-52.

     [Crossref] [Google Scholar] [PubMed]

204. Morrison DK, Kaplan DR, Escobedo JA, Rapp UR, Roberts TM, Williams LT,et al. Direct activation of the serine/threonine kinase activity of Raf-1 through tyrosine phosphorylation by the PDGF beta-receptor. Cell. 1989;58(4):649-657.

     [Crossref] [Google Scholar] [PubMed]

205. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990;61(2):203-212.

     [Crossref] [Google Scholar] [PubMed]

206. Trenker R, Jura N. Receptor tyrosine kinase activation: From the ligand perspective. Curr Opin Cell Biol. 2020;63:174-185.

     [Crossref] Google Scholar] [PubMed]

207. Ségaliny AI, Tellez-Gabriel M, Heymann MF, Heymann D. Receptor tyrosine kinases: Characterisation, mechanism of action and therapeutic interests for bone cancers. J Bone Oncol. 2015;4(1):1-12.

     [Crossref] [ Google Scholar] [PubMed]

208. Ferreira IG, Pucci M, Venturi G, Malagolini N, Chiricolo M, Dall'Olio F, et al. Glycosylation as a main regulator of growth and death factor receptors signaling. Int J Mol Sci. 2018;19(2):580.

     [Crossref] [Google Scholar] [PubMed]

209. Mendelsohn R, Cheung P, Berger L, Partridge E, Lau K, Datti A, et al. Complex N-glycan and metabolic control in tumor cells. Cancer Res. 2007;67(20):9771-9780.

     [Crossref] [Google Scholar] [PubMed]

210. Fujitani N, Uehara Y, Ariki S, Hashimoto U, Mukai J, Hasegawa Y, et al. Site-specific glycosylation analysis of epidermal growth factor receptor 2 (ErbB2): Exploring structure and function toward therapeutic targeting. Glycobiology. 2024;34(3):cwad100

     [Crossref] [Google Scholar] [PubMed]

211. Gędaj A, Gregorczyk P, Żukowska D, Chorążewska A, Ciura K, Kalka M, et al. Glycosylation of FGF/FGFR: An underrated sweet code regulating cellular signaling programs.Cytokine Growth Factor Rev. 2024;77:39-55

     [Crossref] [Google Scholar] [PubMed]

212. Chandler KB, Leon DR, Meyer RD, Rahimi N, Costello CE. Site-specific n-glycosylation of endothelial cell receptor tyrosine kinase VEGFR-2. J Proteome Res. 2017;16(2):677-688.

     [Crossref] [Google Scholar] [PubMed]

213. Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, et al. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell. 2007;129(1):123-134.

     [Crossref] [Google Scholar] [PubMed]

214. Taniguchi N. A sugar-coated switch for cellular growth and arrest. Nat Chem Biol. 2007;3(6):307-309.

     [Crossref] [Google Scholar] [PubMed]

215. Liu X, Wang P, Zhang C, Ma Z. Epidermal Growth Factor Receptor (EGFR): A rising star in the era of precision medicine of lung cancer. Oncotarget. 2017;8(30):50209-50220.

     [Crossref] [Google Scholar] [PubMed]

216. Fernandes H, Cohen S, Bishayee S. Glycosylation-induced conformational modification positively regulates receptor-receptor association: A study with an aberrant epidermal growth factor receptor (EGFRvIII/DeltaEGFR) expressed in cancer cells. J Biol Chem. 2001;276(7):5375-5383.

     [Crossref] [Google Scholar] [PubMed]

217. Wang XQ, Sun P, O'Gorman M, Tai T, Paller AS. Epidermal growth factor receptor glycosylation is required for ganglioside GM3 binding and GM3-mediated suppression [correction of suppresion] of activation. Glycobiology. 2001;11(7):515-522.

     [Crossref] [Google Scholar] [PubMed]

218. Soderquist AM, Carpenter G. Glycosylation of the epidermal growth factor receptor in A-431 cells. The contribution of carbohydrate to receptor function. J Biol Chem. 1984;259(20):12586-12594.

     [Crossref] [Google Scholar] [PubMed]

219. Yamabhai M, Anderson RG. Second cysteine-rich region of epidermal growth factor receptor contains targeting information for caveolae/rafts. J Biol Chem. 2002;277(28):24843-24846.

     [Crossref] [Google Scholar] [PubMed]

220. Tsuda T, Ikeda Y, Taniguchi N. The Asn-420-linked sugar chain in human epidermal growth factor receptor suppresses ligand-independent spontaneous oligomerization. Possible role of a specific sugar chain in controllable receptor activation. J Biol Chem. 2000;275(29):21988-21994.

     [Crossref] [Google Scholar] [PubMed]

221. Kaszuba K, Grzybek M, Orłowski A, Danne R, Róg T, Simons K, et al. N-Glycosylation as determinant of epidermal growth factor receptor conformation in membranes. Proc Natl Acad Sci USA. 2015;112(14):4334-4339.

     [Crossref] [Google Scholar] [PubMed]

222. Liu YC, Yen HY, Chen CY, Chen CH, Cheng PF, Juan YH, et al. Sialylation and fucosylation of epidermal growth factor receptor suppress its dimerization and activation in lung cancer cells. Proc Natl Acad Sci USA. 2011;108(28):11332-11337.

     [Crossref] [Google Scholar] [PubMed]

223. Hu X, Tang F, Liu P, Zhong T, Yuan F, He Q, et al. Structural and functional insight into the glycosylation impact upon the hgf/c-Met signaling pathway. Front Cell Dev Biol. 2020;8:490.

     [Crossref] [Google Scholar] [PubMed]

224. Contessa JN, Bhojani MS, Freeze HH, Rehemtulla A, Lawrence TS. Inhibition of N-linked glycosylation disrupts receptor tyrosine kinase signaling in tumor cells. Cancer Res. 2008;68(10):3803-3809.

     [Crossref] [Google Scholar] [PubMed]

225. Lemmon MA, Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell. 2010;141(7):1117-1134.

     [Crossref] [Google Scholar] [PubMed]

226. Suzuki T, Cummings RD, Aebi M, Parodi A. Glycans in glycoprotein quality control. Cold Spring Harbor Lab Press.

     [Crossref] [Google Scholar] [PubMed]

227. Caramelo JJ, Parodi AJ. Getting in and out from calnexin/calreticulin cycles. J Biol Chem. 2008;283(16):10221-10225.

     [Crossref] [Google Scholar] [PubMed]

228. Cummings RD, Etzler ME, Ramya TNC, Esko JD, Varki A, et al. Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. Chapter 32. 
229. Barbui T, Thiele J, Gisslinger H, Finazzi G, Vannucchi AM, Tefferi A, et al. The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood Rev. 2016;30(6):453-459.

     [Crossref] [Google Scholar] [PubMed]

230. Prins D, Arias CG, Klampfl T, Grinfeld J, Green AR. Mutant calreticulin in the myeloproliferative neoplasms. Hemasphere. 2020;4(1):e333.

     [Crossref] [Google Scholar] [PubMed]

231. Bhave RR, Mesa R, Grunwald MR. Top advances of the year: Myeloproliferative neoplasms. Cancer. 2023;129(23):3685-3691.

     [Crossref] [Google Scholar] [PubMed]

232. Elf S, Abdelfattah NS, Chen E, Perales Patón J, Rosen EA, Ko A, et al. Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov. 2016; 6(4): 368-381.

     [Crossref] [Google Scholar] [PubMed]

233. Chachoua I, Pecquet C, El Khoury M, Nivarthi H, Albu RI, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016; 127(10): 1325-1335.

     [Crossref] [Google Scholar] [PubMed]

234. Elf S, Abdelfattah NS, Baral AJ, Beeson D, Rivera JF, Ko A, et al. Defining the requirements for the pathogenic interaction between mutant calreticulin and MPL in MPN. Blood. 2018;131(7):782-786.

     [Crossref] [ Google Scholar] [PubMed]

235. Lau WW, Hannah R, Green AR, Gottgens B. The JAK-STAT signaling pathway is differentially activated in CALR-positive compared with JAK2V617F-positive ET patients. Blood. 2015; 125(10): 1679-1681.

     [Crossref][ Google Scholar] [PubMed]

236. Marty C, Pecquet C, Nivarthi H, El Khoury M, Chachoua I, Tulliez M, et al. Calreticulin mutants in mice induce an MPL-dependent thrombocytosis with frequent progression to myelofibrosis. Blood. 2016; 127(10): 1317-1324.

     [Crossref] [Google Scholar] [PubMed]

237. Nivarthi H, Chen D, Cleary C, Kubesova B, Jäger R, Bogner E, et al. Thrombopoietin receptor is required for the oncogenic function of CALR mutants. Leukemia. 2016; 30(8): 1759-1763.

     [Google Scholar] [PubMed]

238. Sanmartín Martínez J, Wiersma VR, Marneth AE. The sweet symphony of N-glycans in myeloid malignancies. Front Hematol. 2024;3:1415618.

     [Crossref] [Google Scholar]

239. Kramer F, Mullally A. Antibody targeting of mutant calreticulin in myeloproliferative neoplasms. J Cell Mol Med. 2024;28(5):e17896.

     [Crossref] [Google Scholar] [PubMed]

240. Liu L, Zhao M, Jin X, Ney G, Yang KB, Peng F, et al. Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells. Nat Cell Biol. 2019;21(3):328-337.

     [Crossref] [Google Scholar] [PubMed]

241. Khateb A, Ronai ZA. Unfolded protein response in leukemia: From basic understanding to therapeutic opportunities. Trends Cancer. 2020;6(11):960-973.

     [Crossref] [Google Scholar] [PubMed]

242. Schmidt Arras DE, Böhmer A, Markova B, Choudhary C, Serve H, Böhmer FD. Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases. Mol Cell Biol. 2005;25:3690-3703.

     [Crossref] [Google Scholar] [PubMed]

243. Schmidt-Arras D, Bohmer SA, Koch S, Muller JP, Blei L, Cornils H, et al. Anchoring of FLT3 in the endoplasmic reticulum alters signaling quality. Blood. 2009;113(15):3568–3576.

     [Crossref] [Google Scholar] [PubMed]

244. Schmidt-Arras DE, Böhmer A, Markova B, Choudhary C, Serve H, Böhmer FD. Tyrosine phosphorylation regulates maturation of receptor tyrosine kinases. Mol Cell Biol 2005;25(9):3690–3703. 

     [Crossref] [Google Scholar] [PubMed]

245. Marcotegui N, Romero Murillo S, Marco Sanz J, Peris I, Berrozpe BS, Vicente C, et al. Set Protein Is Involved In FLT3 Membrane trafficking. Cancers (Basel). 2023;15(8):2233.

     [Crossref] [Google Scholar] [PubMed]

246. Hu X, Chen F. Targeting on glycosylation of mutant FLT3 in acute myeloid leukemia. Hematology. 2019;24(1):651-660.

     [Crossref] [Google Scholar] [PubMed]

247. Tsitsipatis D, Jayavelu AK, Muller JP, Bauer R, Schmidt Arras D, Mahboobi S, et al. Synergistic killing of FLT3ITD-positive AML cells by combined inhibition of tyrosine-kinase activity and N-glycosylation. Oncotarget. 2017;8(16):26613-26624.

     [Crossref] [Google Scholar] [PubMed]

248. Williams AB, Li L, Nguyen B, Brown P, Levis M, Small D, et al. Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia. Blood. 2012;120(15):3069-3079.

     [Crossref] [Google Scholar] [PubMed]

249. Larrue C, Saland E, Vergez F, Serhan N, Delabesse E, Mansat-De Mas V, et al. Antileukemic activity of 2-deoxy-d-glucose through inhibition of n-linked glycosylation in acute myeloid leukemia with flt3-itd or c-kit mutations. Mol Cancer Ther. 2015;14(10):2364-2373.

     [Crossref] [Google Scholar] [PubMed]

250. DeSalvo J, Kuznetsov JN, Du J, Leclerc GM, Leclerc GJ, Lampidis TJ, et al. Inhibition of Akt potentiates 2-DG-induced apoptosis via downregulation of UPR in acute lymphoblastic leukemia. Mol Cancer Res. 2012;10(7):969–978.

     [Crossref] [Google Scholar] [PubMed]

251. Leclerc GM, Leclerc GJ, Kuznetsov JN, DeSalvo J, Barredo JC. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts. PLoS One 2013;8(8):e74420.

     [Crossref] [Google Scholar] [PubMed]

252. Zhang D, Li J, Wang F, Hu J, Wang S, Sun Y, et al. 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett. 2014;355(2):176-183.

     [Crossref] [Google Scholar] [PubMed]

253. Li Y, Zeng P, Xiao J, Huang P, Liu P. Modulation of energy metabolism to overcome drug resistance in chronic myeloid leukemia cells through induction of autophagy. Cell Death Discov. 2022;8(1):212.

     [Crossref] [Google Scholar] [PubMed]

254. Toshihiko Toyofuku, Takako Ishikawa, Satoshi Nojima, Atsushi Kumanogoh. Efficacy against lung cancer is augmented by combining aberrantly n-glycosylated t cells with a chimeric antigen receptor targeting fragile x mental retardation 1 neighbor. J Immunol. 2024;212(5):917-927.

     [Crossref] [Google Scholar] [PubMed]

255. Sasawatari S, Okamoto Y, Kumanogoh A, Toyofuku T. Blockade of n-glycosylation promotes antitumor immune response of t cells. J Immunol. 2020;204(5):1373-1385.

     [Crossref] [Google Scholar] [PubMed]

256. Cerliani JP, Blidner AG, Toscano MA, Croci DO, Rabinovich GA. Translating the 'sugar code' into immune and vascular signaling programs. Trends Biochem Sci. 2017;42(4):255-273.

     [Crossref] [Google Scholar] [PubMed]

257. Arcaro A, Grégoire C, Bakker TR, Baldi L, Jordan M, Goffin L, et al. CD8beta endows CD8 with efficient coreceptor function by coupling T cell receptor/CD3 to raft-associated CD8/p56(lck) complexes. J Exp Med. 2001;194(10):1485-1495.

     [Crossref] [Google Scholar] [PubMed]

258. Holler PD, Kranz DM. Quantitative analysis of the contribution of TCR/pepMHC affinity and CD8 to T cell activation. Immunity. 2003;18(2):255-264.

     [Crossref] [Google Scholar] [PubMed]

259. Demotte N, Stroobant V, Courtoy PJ, Van Der Smissen P, Colau D, Luescher IF, et al. Restoring the association of the T cell receptor with CD8 reverses anergy in human tumor-infiltrating lymphocytes. Immunity. 2008;28(3):414-424.

     [Crossref] [Google Scholar] [PubMed]

260. Kearns FL, Rosenfeld MA, Amaro RE. Breaking Down the Bottlebrush: Atomically Detailed Structural Dynamics of Mucins. J Chem Inf Model. 2024;64(20):7949-7965.

     [Crossref] [Google Scholar] [Pubmed]

261. Wardman JF, Sim L, Liu J, Howard TA, Geissner A, Danby PM, et al. A high-throughput screening platform for enzymes active on mucin-type O-glycoproteins. Nat Chem Biol. 2023;19(10):1246-1255.

     [Crossref] [Google Scholar] [PubMed]

262. Ju T, Aryal RP, Kudelka MR, Wang Y, Cummings RD. The cosmc connection to the Tn antigen in cancer. Cancer Biomark. 2014;14(1):63-81.

     [Crossref] [Google Scholar] [PubMed]

263. Berois N, Blanc E, Ripoche H, Mergui X, Trajtenberg F, Cantais S, et al. ppGalNAc-T13: A new molecular marker of bone marrow involvement in neuroblastoma. Clin Chem. 2006;52(9):1701-1712.

     [Crossref] [Google Scholar] [PubMed]

264. Freire T, Berois N, Sóñora C, Varangot M, Barrios E, Osinaga E,et al. UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 6 (ppGalNAc-T6) mRNA as a potential new marker for detection of bone marrow-disseminated breast cancer cells. Int J Cancer. 2006;119(6):1383-1388

     [Crossref] [Google Scholar] [PubMed]

265. Patani N, Jiang WE, Mokbel K. Prognostic utility of glycosyltransferase expression in breast cancer. Cancer Genomics Proteomics. 2008;5(6):333-340.

     [Google Scholar] [PubMed]

266. Gomes J, Marcos NT, Berois N, Osinaga E, Magalhães A, Pinto-de-Sousa J,  et al. Expression of UDP-N-acetyl-D-galactosamine: Polypeptide N-acetylgalactosaminyltransferase-6 in gastric mucosa, intestinal metaplasia, and gastric carcinoma. J Histochem Cytochem. 2009;57(1):79-86.

     [Crossref] [Google Scholar] [PubMed]

267. Shibao K, Izumi H, Nakayama Y, Ohta R, Nagata N, Nomoto M, et al. Expression of UDP-N-acetyl-alpha-D-galactosamine-polypeptide galNAc N-acetylgalactosaminyl transferase-3 in relation to differentiation and prognosis in patients with colorectal carcinoma. Cancer. 2002;94(7):1939-1946.

     [Crossref] [Google Scholar] [PubMed]

268. Ishikawa M, Kitayama J, Nariko H, Kohno K, Nagawa H. The expression pattern of UDP-N-acetyl-alpha-d-galactosamine: Polypeptide N-acetylgalactosaminyl transferase-3 in early gastric carcinoma. J Surg Oncol. 2004;86(1):28-33.

     [Crossref] [Google Scholar] [PubMed]

269. Yamamoto S, Nakamori S, Tsujie M, Takahashi Y, Nagano H, Dono K, et al. Expression of uridine diphosphate N-acetyl-alpha-D-galactosamine: Polypeptide N-acetylgalactosaminyl transferase 3 in adenocarcinoma of the pancreas. Pathobiology. 2004;71(1):12-18.

     [Crossref] [Google Scholar] [PubMed]

270. Taniuchi K, Cerny RL, Tanouchi A, Kohno K, Kotani N, Honke K et al. Overexpression of GalNAc-transferase GalNAc-T3 promotes pancreatic cancer cell growth. Oncogene. 2011;30(49):4843-4854.

     [Crossref] [Google Scholar] [PubMed]

271. Inoue T, Eguchi T, Oda Y, Nishiyama K, Fujii K, Izumi H, et al. Expression of GalNAc-T3 and its relationships with clinicopathological factors in 61 extrahepatic bile duct carcinomas analyzed using stepwise sections-special reference to its association with lymph node metastases-. Mod Pathol. 2007;20(2):267-276.

     [Crossref] [Google Scholar] [PubMed]

272. Landers KA, Burger MJ, Tebay MA, Purdie DM, Scells B, Samaratunga H, et al. Use of multiple biomarkers for a molecular diagnosis of prostate cancer. Int J Cancer. 2005;114(6):950-956.

     [Crossref] [Google Scholar] [PubMed]

273. Miyahara N, Shoda J, Kawamoto T, Furukawa M, Ueda T, Todoroki T, et al. Expression of UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase isozyme 3 in the subserosal layer correlates with postsurgical survival of pathological tumor stage 2 carcinoma of the gallbladder. Clin Cancer Res. 2004;10(6):2090-2099.

     [Crossref] [Google Scholar] [PubMed]

274. Tumoglu B, Keelaghan A, Avci FY. Tn antigen interactions of macrophage galactose-type lectin (MGL) in immune function and disease. Glycobiology. 2023;33(11):879-887.

     [Crossref] [Google Scholar] [PubMed]

275. Radhakrishnan P, Dabelsteen S, Madsen FB, Francavilla C, Kopp KL, Steentoft C, et al. Immature truncated O-glycophenotype of cancer directly induces oncogenic features. Proc Natl Acad Sci USA. 2014;111(39):E4066-E4075.

     [Crossref] [Google Scholar] [PubMed]

276. Bergstrom K, Liu X, Zhao Y, Gao N, WuQ, Song K, et al. Defective intestinalmucin-1 type o-glycosylation causes spontaneouscolitis-associated cancer in mice. Gastroenterology. 2016;151:152-164.

     [Crossref] [Google Scholar] [PubMed]

277. Gao N, Bergstrom K, Fu J, Xie B, Chen W, Xia L, et al. Loss of intestinal O-glycanspromotes spontaneous duodenal tumors. Am J Physiol Gastrointest Liver Physiol. 2016;311:G7483.

     [Crossref] [Google Scholar] [PubMed]

278. Bagdonaite I, Pallesen EM, Ye Z, Vakhrushev SY, Marinova IN, Nielsen MI, et al. O-glycan initiation directs distinct biological pathways and controls epithelial differentiation. EMBO Rep. 2020;21(6):e48885.

     [Crossref] [Google Scholar] [PubMed]

279. Dabelsteen S, Pallesen EMH, Marinova IN, Nielsen MI, Adamopoulou M, Rømer TB, et al. Essential functions of glycans in human epithelia dissected by a crispr-cas9-engineeredhuman organotypic skin model. Dev Cell. 2020;54:669-684.

     [Crossref] [Google Scholar] [PubMed]

280. Madsen CB, Lavrsen K, Steentoft C, Vester Christensen MB, Clausen H, WandallHH, et al. Glycan elongation beyond the mucin associated Tn antigen protects tumor cells from immune-mediated killing. PLoS One. 2013;8:e72413.

     [Crossref] [Google Scholar] [PubMed]

281. Mathiesen CBK, Carlsson MC, Brand S, Möller SR, Idorn M, thor Straten P, et al. Genetically engineered cell factories produce glycoengineered vaccines that target antigen-presenting cells and reduce antigen-specific T-cell reactivity. J Allergy Clin Immunol. 2018;1426:1983-1987.

     [Crossref] [Google Scholar] [PubMed]

282. Corelissen LAM, Blanas A, Zaal A, van der Horst JC, Kruijssen LJW, O'Toole T, et al. Tn antigen expression contributes to an immune suppressive microenvironment and drivestumor growth in colorectal cancer. Front Oncol. 2020;10:1622

     [Crossref] [Google Scholar] [PubMed]

283. Zaal A, Li RJE, Lübbers J, Bruijns SCM, Kalay H, van Kooyk Y, et al. Activation ofthe c-type lectin mgl by terminal gainac ligands reduces the glycolytic activity of humandendritic cells. Front Immunol. 2020:11:305

     [Crossref] [Google Scholar] [PubMed]

284. Libisch MG, Casás M, Chiribao M, Moreno P, Cayota A, Osinaga E, et al. GALNT11 as a new molecular marker in chronic lymphocytic leukemia. Gene. 2014;533(1):270-279

     [Crossref] [Google Scholar] [PubMed]

285. Yu LG. The oncofetal thomsen-friedenreich carbohydrate antigen in cancer progression. Glycoconj J. 2007;24(8):411-420.

     [Crossref] [Google Scholar] [PubMed]

286. Yu LG. The oncofetal thomsen-friedenreich carbohydrate antigen in cancer progression. Glycoconj J. 2007;24(8):411-420.

     [Crossref] [Google Scholar] [PubMed]

287. Brockhausen I, Schachter H, Stanley P. O-GalNAc Glycans. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Chapter 9. 
288. Iwai T, Inaba N, Naundorf A, Zhang Y, Gotoh M, Iwasaki H, et al. Molecular cloning and characterization of a novel UDP-GlcNAc:GalNAc-peptide beta1,3-N-acetylglucosaminyltransferase (beta 3Gn-T6), an enzyme synthesizing the core 3 structure of O-glycans. J Biol Chem. 2002;277(15):12802-12809. 

     [Crossref] [Google Scholar] [PubMed]

289. Yang JM, Byrd JC, Siddiki BB, Chung YS, Okuno M, Sowa M, et al. Alterations of O-glycan biosynthesis in human colon cancer tissues. Glycobiology. 1994;4(6):873-884.

     [Crossref] [Google Scholar] [PubMed]

290. Kim YS. Mucin glycoproteins in colonic neoplasia. Keio J Med. 1998;47(1):10-18.

     [Crossref] [Google Scholar] [PubMed]

291. Brockhausen I. Pathways of O-glycan biosynthesis in cancer cells. Biochim Biophys Acta. 1999;1473(1):67-95.

     [Crossref] [Google Scholar] [PubMed]

292. Gill DJ, Clausen H, Bard F. Location, location, location: New insights into O-GalNAc protein glycosylation. Trends Cell Biol. 2011;21(3):149-158.

     [Crossref] [Google Scholar] [PubMed]

293. Ellies LG, Tsuboi S, Petryniak B, Lowe JB, Fukuda M, Marth JD, et al. Core 2 oligosaccharide biosynthesis distinguishes between selectin ligands essential for leukocyte homing and inflammation. Immunity. 1998;9(6):881-890.

     [Crossref] [Google Scholar] [PubMed]

294. Kojima Y, Yoneyama T, Hatakeyama S, Mikami J, Sato T, Mori K, et al. Detection of core2 β-1,6-n-acetylglucosaminyltransferase in post-digital rectal examination urine is a reliable indicator for extracapsular extension of prostate cancer. PLoS One. 2015;10(9):e0138520.

     [Crossref] [Google Scholar] [PubMed]

295. Ju T, Otto VI, Cummings RD. The Tn antigen-structural simplicity and biological complexity. Angew Chem Int Ed Engl. 2011;50(8):1770-1791.

     [Crossref] [Google Scholar] [PubMed]

296. Vanderplasschen A, Markine-Goriaynoff N, Lomonte P, Suzuki M, Hiraoka N, Yeh JC, et al. A multipotential beta -1,6-N-acetylglucosaminyl-transferase is encoded by bovine herpesvirus type 4. Proc Natl Acad Sci USA. 2000;97(11):5756-5761.

     [Crossref] [Google Scholar] [PubMed]

297. Mahoney KE, Chang V, Lucas TM, Maruszko K, Malaker SA. Optimized mucin-selective enrichment strategy to probe the mucinome. bioRxiv. 2023.

     [Crossref] [Google Scholar] [PubMed]

298. Steentoft C, Vakhrushev SY, Joshi HJ, Kong Y, Vester Christensen MB, Schjoldager KT, et al. Precision mapping of the human O-GalNAc glycoproteome through SimpleCell technology. EMBO J. 2013;32(10):1478–1488. 

     [Crossref] [Google Scholar] [PubMed]

299. Kudelka MR, Ju T, Heimburg-Molinaro J, Cummings RD. Simple sugars to complex disease--mucin-type O-glycans in cancer. Adv Cancer Res. 2015;126:53-135.

     [Crossref] [Google Scholar] [PubMed]

300. Radziejewska I. Tumor-associated carbohydrate antigens of MUC1-Implication in cancer development. Biomed Pharmacother. 2024;174:116619.

     [Crossref] [Google Scholar] [PubMed]

301. Park S, Colville MJ, Paek JH, Shurer CR, Singh A, Secor EJ, et al. Immunoengineering can overcome the glycocalyx armour of cancer cells. Nat Mater. 2024;23(3):429-438.

     [Crossref] [Google Scholar] [PubMed]

302. Beatson R, Burchell JM. A mucin degrader for cancer therapy. Nat Biotechnol. 2024;42(4):572-573

     [Crossref] [Google Scholar] [PubMed]

303. Läubli H, Borsig L. Altered cell adhesion and glycosylation promote cancer immune suppression and metastasis. Front Immunol. 2019;10:2120.

     [Crossref] [Google Scholar] [PubMed]

304. Taleb V, Liao Q, Narimatsu Y, García García A, Compañón I, Borges RJ, et al. Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut. Nat Commun. 2022;13(1):4324.

     [Crossref] [Google Scholar] [PubMed]

305. Peng W, Giesbers KC, Šiborová M, Beugelink JW, Pronker MF, Schulte D, et al. Reverse-engineering the anti-MUC1 antibody 139H2 by mass spectrometry-based de novo sequencing. Life Sci Alliance. 2024;7(6):e202302366.

     [Crossref] [Google Scholar] [PubMed]

306. Lan Y, Ni W, Tai G. Expression of MUC1 in different tumours and its clinical significance (Review). Mol Clin Oncol. 2022;17(6):161.

     [Crossref] [Google Scholar] [PubMed]

307. Srivastava AK, Guadagnin G, Cappello P, Novelli F. Post-translational modifications in tumor-associated antigens as a platform for novel immuno-oncology therapies. Cancers (Basel). 2022;15(1):138. 

     [Crossref] [Google Scholar] [PubMed]

308. van Vliet SJ, van Liempt E, Saeland E, Aarnoudse CA, Appelmelk B, Irimura T, et al. Carbohydrate profiling reveals a distinctive role for the C-type lectin MGL in the recognition of helminth parasites and tumor antigens by dendritic cells. Int Immunol. 2005;17(5):661-669. 

     [Crossref] [Google Scholar] [PubMed]

309. Burchell JM, Mungul A, Taylor Papadimitriou J. O-linked glycosylation in the mammary gland: Changes that occur during malignancy. J Mammary Gland Biol Neoplasia. 2001;6(3):355-364.

     [Crossref] [Google Scholar] [PubMed]

310. Beckwith DM, Cudic M. Tumor-associated O-glycans of MUC1: Carriers of the glyco-code and targets for cancer vaccine design. Semin Immunol. 2020;47:101389.

     [Crossref] [Google Scholar] [PubMed]

311. Engering A, Geijtenbeek TB, van Kooyk Y. Immune escape through C-type lectins on dendritic cells.Trends Immunol. 2002;23(10):480-485.

     [Crossref] [Google Scholar] [PubMed]

312. Gao T, Cen Q, Lei H. A review on development of MUC1-based cancer vaccine. Biomed Pharmacother. 2020;132(110888).

     [Crossref] [Google Scholar] [PubMed]

313. Sigismund S, Avanzato D, Lanzetti L. Emerging functions of the EGFR in cancer. Mol Oncol. 2018;12(1):3-20.

     [Crossref] [Google Scholar] [PubMed]

314. O'Leary C, Gasper H, Sahin KB, Tang M, Kulasinghe A, Adams MN, et al. Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC). Pharmaceuticals. 2020;13(10):273.

     [Crossref] [Google Scholar] [PubMed]

315. Engel BJ, Bowser JL, Broaddus RR, Carson DD. MUC1 stimulates EGFR expression and function in endometrial cancer. Oncotarget. 2016;7(22):32796-32809

     [Crossref] [Google Scholar] [PubMed]

316. Morese PA, Anthony N, Bodnarchuk M, Jennings C, Martin MP, Noble RA, et al. Targeting cytotoxic agents through egfr-mediated covalent binding and release. J Med Chem. 2023;66(17):12324-12341.

     [Crossref] [Google Scholar] [PubMed]

317. Chen W, Zhang Z, Zhang S, Zhu P, Ko JK, Yung KK, et al. MUC1: Structure, function, and clinic application in epithelial cancers. Int J Mol Sci. 2021;22(12):6567.

     [Crossref] [Google Scholar] [PubMed]

318. Brossart P, Schneider A, Dill P, Schammann T, Grunebach F, Wirths S, et al. The epithelial tumor antigen MUC1 is expressed in hematological malignancies and is recognized by MUC1-specific cytotoxic T-Lymphocytes. Cancer Res. 2001;61:6846-6850. 

     [Google Scholar] [PubMed]

319. Rassidakis GZ, Goy A, Medeiros LJ, Jiang Y, Thomaides A, Remache Y, et al. Prognostic significance of MUC-1 expression in systemic anaplastic large cell lymphoma. Clin Cancer Res. 2003;6:2213-2220.

     [Google Scholar] [PubMed]

320. Jain S, Stroopinsky D, Yin L, Rosenblatt J, Alam M, Bhargava P, et al. Mucin 1 is a potential therapeutic target in cutaneous T-cell lymphoma. Blood 2015;126:354-362.

     [Crossref] [Google Scholar] [PubMed]

321. Miyoshi E, Moriwaki K, Nakagawa T. Biological function of fucosylation in cancer biology. J Biochem. 2008;143:725-729.

     [Crossref] [Google Scholar] [PubMed]

322. Pan Q, Xie Y, Zhang Y, Guo X, Wang J, Liu M, et al. EGFR core fucosylation, induced by hepatitis C virus, promotes TRIM40-mediated-RIG-I ubiquitination and suppresses interferon-I antiviral defenses. Nat Commun. 2024;15(1):652.

     [Crossref] [Google Scholar] [PubMed]

323. Li W, Yu R, Ma B, Yang Y, Jiao X, Liu Y, et al. Core fucosylation of IgG B cell receptor is required for antigen recognition and antibody production. J Immunol. 2015;194(6):2596-2606.

     [Crossref] [Google Scholar] [PubMed]

324. Wang X, Inoue S, Gu J, Miyoshi E, Noda K, Li W, et al. Dysregulation of TGF-beta1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice. Proc Natl Acad Sci USA. 2005;102(44):15791-15796.

     [Crossref] [Google Scholar] [PubMed]

325. Mimura Y, Katoh T, Saldova R, O’Flaherty R, Izumi T, Mimura-Kimura Y, et al. Glycosylation engineering of therapeutic IgG antibodies: Challenges for the safety, functionality and efficacy. Protein Cell. 2018;9(1):47-62.

     [Crossref] [Google Scholar] [PubMed]

326. Hirakawa M, Takimoto R, Tamura F, Yoshida M, Ono M, Murase K, et al. Fucosylated TGF-β receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells. Br J Cancer.m 2014;110(1):156-163.

     [Crossref] [Google Scholar] [PubMed]

327. de Haan N, Reiding KR, Driessen G, van der Burg M, Wuhrer M. Changes in healthy human Igg fc-glycosylation after birth and during early childhood. J Proteome Res. 2016;15(6):1853-1861.

     [Crossref] [Google Scholar] [PubMed]

328. Shinkawa T, Nakamura K, Yamane N, Shoji Hosaka E, Kanda Y, Sakurada M, et al. The absence of fucose but not the presence of galactose or bisecting N-acetylglucosamine of human IgG1 complex-type oligosaccharides shows the critical role of enhancing antibody-dependent cellular cytotoxicity. J Biol Chem. 2003;278(5):3466-3473.

     [Crossref] [Google Scholar] [PubMed]

329. Veillon L, Fakih C, Abou-El Hassan H, Kobeissy F, Mechref Y. Glycosylation changes in brain cancer. ACS Chem Neurosci. 2018;9(1):51-72

     [Crossref] [Google Scholar] [PubMed]

330. Aldonza MBD, Cha J, Yong I, Ku J, Sinitcyn P, Lee D, et al. Multi-targeted therapy resistance via drug-induced secretome fucosylation. Elife. 2023;12:e75191.

     [Crossref] [Google Scholar] [PubMed]

331. Yang Q, Zhang R, Cai H, Wang LX. Revisiting the substrate specificity of mammalian α1,6-fucosyltransferase reveals that it catalyzes core fucosylation of N-glycans lacking α1,3-arm GlcNAc. J Biol Chem. 2017;292(36):14796-14803

     [Crossref] [Google Scholar] [PubMed]

332. Chen CY, Jan YH, Juan YH, Yang CJ, Huang MS, Yu CJ, et al. Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer. Proc Natl Acad Sci USA. 2013;110(2):630-635.

     [Crossref] [Google Scholar] [PubMed]

333. Wang X, Chen J, Li QK, Peskoe SB, Zhang B, Choi C, et al. Overexpression of α (1,6) fucosyltransferase associated with aggressive prostate cancer. Glycobiology. 2014;24(10):935-944.

     [Crossref] [Google Scholar] [PubMed]

334. Noda K, Miyoshi E, Uozumi N, Yanagidani S, Ikeda Y, Gao CX, et al. Gene expression of alpha1-6 fucosyltransferase in human hepatoma tissues: A possible implication for increased fucosylation of alpha-fetoprotein. Hepatology.1998;28(4):944-952.

     [Crossref] [Google Scholar] [PubMed]

335. Miyoshi E, Uozumi N, Noda K, Hayashi N, Hori M, Taniguchi N, et al. Expression of alpha1-6 fucosyltransferase in rat tissues and human cancer cell lines. Int J Cancer. 1997;72(6):1117-1121.

     [Crossref] [Google Scholar] [PubMed]

336. Noda K, Miyoshi E, Uozumi N, Gao CX, Suzuki K, Hayashi N, et al. High expression of alpha-1-6 fucosyltransferase during rat hepatocarcinogenesis. Int J Cancer. 1998;75(3):444-450.

     [Crossref] [Google Scholar] [PubMed]

337. Muinelo-Romay L, Vázquez Martín C, Villar Portela S, Cuevas E, Gil Martín E, Fernández Briera A, et al. Expression and enzyme activity of alpha(1,6)fucosyltransferase in human colorectal cancer. Int J Cancer. 2008;123(3):641-646.

     [Crossref] [Google Scholar] [PubMed]

338. Noda M, Okayama H, Kofunato Y, Chida S, Saito K, Tada T, et al. Prognostic role of FUT8 expression in relation to p53 status in stage II and III colorectal cancer. PLoS One. 2018;13(7):e0200315.

     [Crossref] [Google Scholar] [PubMed]

339. Tu CF, Wu MY, Lin YC, Kannagi R, Yang RB. FUT8 promotes breast cancer cell invasiveness by remodeling TGF-β receptor core fucosylation. Breast Cancer Res. 2017;19(1):111.

     [Crossref] [Google Scholar] [PubMed]

340. Sato Y, Nakata K, Kato Y, Shima M, Ishii N, Koji T, et al. Early recognition of hepatocellular carcinoma based on altered profiles of alpha-fetoprotein. N Engl J Med. 1993;328(25):1802-1806.

     [Crossref] [Google Scholar] [PubMed]

341. Aoyagi Y, Isemura M, Suzuki Y, Sekine C, Soga K, Ozaki T, et al. Fucosylated alpha-fetoprotein as marker of early hepatocellular carcinoma. Lancet. 1985;2(8468):1353-1354.

     [Crossref] [Google Scholar] [PubMed]

342. Martin KC, Tricomi J, Corzana F, García García A, Ceballos Laita L, Hicks T, et al. Fucosyltransferase-specific inhibition via next generation of fucose mimetics. Chem Commun (Camb). 2021;57(9):1145-1148.

     [Crossref] [Google Scholar] [PubMed]

343. Blanas A, Sahasrabudhe NM, Rodríguez E, van Kooyk Y, van Vliet SJ. Fucosylated antigens in cancer: An alliance toward tumor progression, metastasis, and resistance to chemotherapy. Front Oncol. 2018;8:39.

     [Crossref] [Google Scholar] [PubMed]

344. Sell S. Cancer-associated carbohydrates identified by monoclonal antibodies. Hum Pathol. 1990;21(10):1003-1019.

     [Crossref] [Google Scholar] [PubMed]

345. Dube DH, Bertozzi CR. Glycans in cancer and inflammation-potential for therapeutics and diagnostics. Nat Rev Drug Discov. 2005;4(6):477-488

     [Crossref] [Google Scholar] [PubMed]

346. Flögel M, Lauc G, Gornik I, Macek B. Fucosylation and galactosylation of IgG heavy chains differ between acute and remission phases of juvenile chronic arthritis. Clin Chem Lab Med. 1998;36(2):99-102.

     [Crossref] [Google Scholar] [PubMed]

347. Gornik I, Maravić G, Dumić J, Flögel M, Lauc G. Fucosylation of IgG heavy chains is increased in rheumatoid arthritis. Clin Biochem. 1999;32(8):605-608.

     [Crossref] [Google Scholar] [PubMed]

348. Hänninen A, Taylor C, Streeter PR, Stark LS, Sarte JM, Shizuru J, et al. Vascular addressins are induced on islet vessels during insulitis in nonobese diabetic mice and are involved in lymphoid cell binding to islet endothelium. J Clin Invest. 1993;92(5):2509-2515.

     [Crossref] [Google Scholar] [PubMed]

349. Mondal N, Dykstra B, Lee J, Ashline DJ, Reinhold VN, Rossi DJ, et al. Distinct human (1,3)-fucosyltransferases drive Lewis-X/sialyl Lewis-X assembly in human cells. J Biol Chem. 2018;293(19):7300-7314. 

     [Crossref] [Google Scholar] [PubMed]

350. Mondal N, Dykstra B, Lee J, Ashline DJ, Reinhold VN, Rossi DJ, et al. Distinct human α(1,3)-fucosyltransferases drive Lewis-X/sialyl Lewis-X assembly in human cells. J Biol Chem. 2018;293(19):7300-7314.

     [Crossref] [Google Scholar] [PubMed]

351. Kanamori A, Kojima N, Uchimura K, Muramatsu T, Tamatani T, Berndt MC, et al. Distinct sulfation requirements of selectins disclosed using cells that support rolling mediated by all three selectins under shear flow: L-selectin prefers carbohydrate 6-sulfation to tyrosine sulfation, whereas p-selectin does not* 210. J Biol Chem. 2002;277(36):32578-32586.

     [Crossref] [Google Scholar] [PubMed]

352. Knibbs RN, Craig RA, Natsuka S, Chang A, Cameron M, Lowe JB, et al. The fucosyltransferase FucT-VII regulates E-selectin ligand synthesis in human T cells. J Cell Biol. 1996;133(4):911-920.

     [Crossref] [Google Scholar] [PubMed]

353. Wagers AJ, Stoolman LM, Kannagi R, Craig R, Kansas GS. Expression of leukocyte fucosyltransferases regulates binding to E-selectin: Relationship to previously implicated carbohydrate epitopes. J Immunol. 1997;159(4):1917-1929.

     [Crossref] [Google Scholar] [PubMed]

354. Ohmori K, Takada A, Ohwaki I, Takahashi N, Furukawa Y, Maeda M, et al. A distinct type of sialyl Lewis X antigen defined by a novel monoclonal antibody is selectively expressed on helper memory T cells. Blood. 1993;82(9):2797-2805.

     [Crossref] [Google Scholar] [PubMed]

355. Furukawa Y, Tara M, Ohmori K, Kannagi R. Variant type of sialyl Lewis X antigen expressed on adult T cell leukemia cells is associated with skin involvement. Cancer Res. 1994;54(24):6533-6538.

     [Google Scholar] [PubMed]

356. Hiraiwa N, Yabuta T, Yoritomi K, Hiraiwa M,  Tanaka Y, Suzuki T, et al.  Transactivation of the fucosyltransferase VII gene by human T-cell leukemia virus type 1 Tax through a variant cAMP-responsive element. Blood. 2003;101(9):3615-3621.

     [Crossref] [Google Scholar] [PubMed]

357. Huynh DT, Tsolova KN, Watson AJ, Khal SK, Green JR, Li D, et al. O-glcnacylation regulates neurofilament-light assembly and function and is perturbed by charcot-marie-tooth disease mutations. Nat Commun. 2023;14(1):6558.

     [Crossref] [Google Scholar] [PubMed]

358. Wulff-Fuentes E, Berendt RR, Massman L, Danner L, Malard F, Vora J, et al. The human O-GlcNAcome database and meta-analysis. Sci Data. 2021;8(1):25.

     [Crossref] [Google Scholar] [PubMed]

359. Wells L, Hart GW. O-GlcNAcylation: A major nutrient/stress sensor that regulates cellular physiology. J Biol Chem. 2024;300(9).

     [Crossref] [Google Scholar] [PubMed]

360. Hart GW. Three decades of research on O-GlcNAcylation-a major nutrient sensor that regulates signaling, transcription and cellular metabolism. Front. Endocrinol. 2014; 5:183.

     [Crossref] [Google Scholar] [PubMed]

361. Hart GW, Akimoto Y. The O-GlcNAc modification. Essent Glycobiol. 2nd edition. 2009.

     [Crossref] [Google Scholar] [PubMed]

362. Mueller T, Ouyang X, Johnson MS, Qian WJ, Chatham JC, Darley-Usmar V, et al. New insights into the biology of protein O-GlcNAcylation: Approaches and observations. Front Aging. 2021; 1:620382.

     [Crossref] [Google Scholar] [PubMed]

363. Mannino MP, Hart GW. The beginner’s guide to O-GlcNAc: From nutrient sensitive pathway regulation to its impact on the immune system. Front Immunol. 2022; 13:828648.

     [Crossref] [Google Scholar] [PubMed]

364. Golks A, Tran TT, Goetschy JF, Guerini D. Requirement for O‐linked N‐acetylglucosaminyltransferase in lymphocytes activation. EMBO J. 2007;26(20):4368-4379.

     [Crossref] [Google Scholar] [PubMed]

365. Ramakrishnan P. O-GlcNAcylation and immune cell signaling: A review of known and a preview of unknown. J Biol Chem. 2024:107349.

     [Crossref] [Google Scholar] [PubMed]

366. Nie H, Yi W. O-GlcNAcylation, a sweet link to the pathology of diseases. J Zhejiang Univ Sci B. 2019;20(5):437-448.

     [Crossref] [Google Scholar] [PubMed]

367. Zachara NE, Akimoto Y, Boyce M, Hart GW. The O-GlcNAc Modification. 4th edition; 2022.

     [Google Scholar]

368. Liu AR, Ramakrishnan P. Regulation of nuclear factor-kappaB function by O-glcNAcylation in inflammation and cancer. Front Cell Dev Biol. 2021;9: 751761.

     [Crossref] [Google Scholar] [PubMed]

369. Akella NM, Ciraku L, Reginato MJ. Fueling the fire: Emerging role of the hexosamine biosynthetic pathway in cancer. BMC Biol. 2019; 17:1-4.

     [Crossref] [Google Scholar] [PubMed]

370. Itkonen HM, Loda M, Mills IG. O-GlcNAc transferase-an auxiliary factor or a full-blown oncogene? Mol Cancer Res. 2021;19(4):555-564.

     [Crossref] [Google Scholar] [PubMed]

371. Ma Z, Vosseller K. Cancer metabolism and elevated O-GlcNAc in oncogenic signaling. J Biol Chem. 2014;289(50):34457-34465.

     [Crossref] [Google Scholar] [PubMed]

372. Fardini Y, Dehennaut V, Lefebvre T, Issad T. O-GlcNAcylation: A new cancer hallmark? Front Endocrinol. 2013;4:99.

     [Crossref] [Google Scholar] [PubMed]

373. Zhu Y, Hart GW. Targeting O-GlcNAcylation to develop novel therapeutics. Mol Aspects Med. 2021; 79:100885.

     [Crossref] [Google Scholar] [PubMed]

374. Tibullo D, Giallongo C, Romano A, Vicario N, Barbato A, Puglisi F, et al. Mitochondrial functions, energy metabolism and protein glycosylation are interconnected processes mediating resistance to bortezomib in multiple myeloma cells. Biomolecules. 2020;10(5):696.

     [Crossref] [Google Scholar] [PubMed]

375. Jin Y, Liang Y, Su Y, Hui L, Liu H, Ding L, et al. Identification of novel combined biomarkers in the diagnosis of multiple myeloma. Hematology. 2021;26(1):964-969.

     [Crossref] [Google Scholar] [PubMed]

376. Shi Y, Tomic J, Wen F, Shaha S, Bahlo A, Harrison R, et al. Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia. 2010;24(9):1588-1598.

     [Crossref] [Google Scholar] [PubMed]

377. Spaner DE. O-GlcNAcylation in chronic lymphocytic leukemia and other blood cancers. Front Immunol. 2021; 12:772304.

     [Crossref] [Google Scholar] [PubMed]

378. Schauer R, Kamerling JP. Exploration of the sialic acid world. Advances in carbohydrate chemistry and biochemistry. 2018;75:1-213.

     [Crossref] [Google Scholar] [PubMed]

379. Läubli H, Nalle SC, Maslyar D. Targeting the siglec-sialic acid immune axis in cancer: Current and future approaches. Cancer Immunol Res. 2022;10(12):1423-1432.

     [Crossref] [Google Scholar] [PubMed]

380. Dedola S, Ahmadipour S, de Andrade P, Baker AN, Boshra AN, Chessa S, et al. Sialic acids in infection and their potential use in detection and protection against pathogens. RSC Chem Biol. 2024;5(3):167-188.

     [Crossref] [Google Scholar] [PubMed]

381. Varki A, Schnaar RL, Schauer R. Sialic acids and other nonulosonic acids. 2017.

     [Crossref] [Google Scholar] [PubMed]

382. Murugesan G, Weigle B, Crocker PR. Siglec and anti-Siglec therapies. Curr Opin Chem Biol. 2021;62: 34-42.

     [Crossref] [Google Scholar] [PubMed]

383. Bhide GP, Colley KJ. Sialylation of N-glycans: Mechanism, cellular compartmentalization and function. Histochem Cell Biol. 2017; 147:149-174.

     [Crossref] [Google Scholar] [PubMed]

384. Verheijen FW. Sialic acid. Lab Guide Methods Biochem Genet. 2008;335-349.

     [Crossref] [Google Scholar]

385. Miyagi T, Takahashi K, Hata K, Shiozaki K, Yamaguchi K. Sialidase significance for cancer progression. Glycoconj J. 2012; 29:567-577. 

     [Crossref] [Google Scholar] [PubMed]

386. Miró L, López J, Guerrero PE, Martínez-Bosch N, Manero-Rupérez N, Moreno M, et al. Sialyltransferase inhibitor ac53faxneu5ac reverts the malignant phenotype of pancreatic cancer cells, and reduces tumor volume and favors t-cell infiltrates in mice. Cancers (Basel). 2022;14(24):6133.

     [Crossref] [Google Scholar] [PubMed]

387. Perez SJ, Fu CW, Li WS. Sialyltransferase inhibitors for the treatment of cancer metastasis: Current challenges and future perspectives. Molecules. 2021;26(18):5673.

     [Crossref] [Google Scholar] [PubMed]

388. Munkley J, Scott E. Targeting aberrant sialylation to treat cancer. Medicines (Basel). 2019;6(4):102.

     [Crossref] [Google Scholar] [PubMed]

389. Huang J, Huang J, Zhang G. Insights into the role of sialylation in cancer metastasis, immunity, and therapeutic opportunity. Cancers. 2022;14(23):5840.

     [Crossref] [Google Scholar] [PubMed]

390. Läubli H, Varki A. Sialic acid–binding immunoglobulin-like lectins (Siglecs) detect self-associated molecular patterns to regulate immune responses. Cell Mol Life Sci. 2020;77(4):593-605.

     [Crossref] [Google Scholar] [PubMed]

391. Varki A. Letter to the glyco-forum: Since there are PAMPs and DAMPs, there must be SAMPs? Glycan “self-associated molecular patterns” dampen innate immunity, but pathogens can mimic them. Glycobiology. 2011;21(9):1121-1124. 

     [Crossref] [Google Scholar] [PubMed]

392. Tharp KM, Park S, Timblin GA, Richards AL, Berg JA, Twells NM, et al. The microenvironment dictates glycocalyx construction and immune surveillance. Res Sq. 2023.

     [Crossref] [Google Scholar] [PubMed]

393. Zhang Z, Wuhrer M, Holst S. Serum sialylation changes in cancer. Glycoconj J. 2018; 35:139-160.

     [Crossref] [Google Scholar] [PubMed]

394. Munkley J. The role of sialyl-Tn in cancer. Int J Mol Sci. 2016;17(3):275.

     [Crossref] [Google Scholar] [PubMed]

395. Yogeeswaran G, Salk PL. Metastatic potential is positively correlated with cell surface sialylation of cultured murine tumor cell lines. Science. 1981;212(4502):1514-1516.

     [Crossref] [Google Scholar] [PubMed]

396. Nag S, Mandal A, Joshi A, Jain N, Srivastava RS, Singh S, et al. Sialyltransferases and neuraminidases: Potential targets for cancer treatment. Diseases. 2022;10(4):114.

     [Crossref] [Google Scholar] [PubMed]

397. Irazoqui FJ, Nores GA. Thomsen-friedenreich disaccharide immunogenicity. Curr Cancer Drug Targets. 2003;3:433–443.

     [Crossref] [Google Scholar] [PubMed]

398. Scott E, Archer Goode E, Garnham R, Hodgson K, Orozco Moreno M, Turner H, et al. ST6GAL1-mediated aberrant sialylation promotes prostate cancer progression. J Pathol. 2023;261(1):71-84.

     [Crossref] [Google Scholar] [PubMed]

399. Hodgson K, Orozco Moreno M, Goode EA, Fisher M, Garnham R, Beatson R, et al. Sialic acid blockade inhibits the metastatic spread of prostate cancer to bone. EBioMedicine. 2024;104.

     [Crossref] [Google Scholar] [PubMed]

400. Hugonnet M, Singh P, Haas Q, von Gunten S. The distinct roles of sialyltransferases in cancer biology and onco-immunology. Front Immunol. 2021; 12:799861.

     [Crossref] [Google Scholar] [PubMed]

401. Garnham R, Geh D, Nelson R, Ramon-Gil E, Wilson L, Schmidt EN, et al. ST3 beta-galactoside alpha-2, 3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer. Commun Biol. 2024;7(1):276.

     [Crossref] [Google Scholar] [PubMed]

402. Kannagi R, Izawa M, Koike T, Miyazaki K, Kimura N. Carbohydrate‐mediated cell adhesion in cancer metastasis and angiogenesis. Cancer Sci. 2004;95(5):377-384.

     [Crossref] [Google Scholar] [PubMed]

403. Villar Portela S, Vazquez Martin C, Muinelo Romay L, Cuevas E, Gil Martin E, Fernandez Briera A. sLea and sLex expression in colorectal cancer: Implications for tumourigenesis and disease prognosis. Histol Histopathol. 2011.

     [Crossref] [Google Scholar] [PubMed]

404. Chachadi VB, Bhat G, Cheng PW. Glycosyltransferases involved in the synthesis of MUC-associated metastasis-promoting selectin ligands. Glycobiology. 2015;25(9):963-975.

     [Crossref] [Google Scholar] [PubMed]

405. Dall'Olio F, Chiricolo M. Sialyltransferases in cancer. Glycoconj J. 2001;18:841-850.

     [Crossref] [Google Scholar] [PubMed]

406. Dobie C, Skropeta D. Insights into the role of sialylation in cancer progression and metastasis. Br J Cancer. 2021;124(1):76-90.

     [Crossref] [Google Scholar] [PubMed]

407. Rao TC, Beggs RR, Ankenbauer KE, Hwang J, Ma VP, Salaita K, et al. ST6Gal-I-mediated sialylation of the epidermal growth factor receptor modulates cell mechanics and enhances invasion. J Biol Chem. 2022;298(4).

     [Crossref] [Google Scholar] [PubMed]

408. Chen JY, Tang YA, Huang SM, Juan HF, Wu LW, Sun YC, et al. A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 2011;71(2):473-483. 

     [Crossref] [Google Scholar] [PubMed]

409. Chiang CH, Wang CH, Chang HC, More SV, Li WS, Hung WC. A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin‐mediated signaling. J Cell Physiol. 2010;223(2):492-499.

     [Crossref] [Google Scholar] [PubMed]

410. Al Saoud R, Hamrouni A, Idris A, Mousa WK, Izneid TA. Recent advances in the development of sialyltransferase inhibitors to control cancer metastasis: A comprehensive review. Biomed Pharmacother. 2023;165:115091.

     [Crossref] [Google Scholar] [PubMed]

411. Smithson M, Irwin R, Williams G, Alexander KL, Smythies LE, Nearing M, et al. Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer. J Biol Chem. 2022;298(3).

     [Crossref] [Google Scholar] [PubMed]

412. Britain CM, Holdbrooks AT, Anderson JC, Willey CD, Bellis SL. Sialylation of EGFR by the ST6Gal-I sialyltransferase promotes EGFR activation and resistance to gefitinib-mediated cell death. J Ovarian Res. 2018;11:1-1.

     [Crossref] [Google Scholar] [PubMed]

413. Fan TC, Yeo HL, Hsu HM, Yu JC, Ho MY, Lin WD, et al. Reciprocal feedback regulation of ST3GAL1 and GFRA1 signaling in breast cancer cells. Cancer Lett. 2018; 434:184-195.

     [Crossref] [Google Scholar] [PubMed]

414. Wang H, Wang X, Li Y, Liao A, Fu B, Pan H, et al. The proteasome inhibitor bortezomib reverses P-glycoprotein-mediated leukemia multi-drug resistance through the NF-κB pathway. Pharmazie. 2012;67(2):187-192. 

     [Crossref] [Google Scholar] [PubMed]

415. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2002;71(1):537-592.

     [Crossref] [Google Scholar] [PubMed]

416. Kourti M, Vavatsi N, Gombakis N, Sidi V, Tzimagiorgis G, Papageorgiou T, et al. Expression of multidrug resistance 1 (MDR1), multidrug resistance-related protein 1 (MRP1), lung resistance protein (LRP), and breast cancer resistance protein (BCRP) genes and clinical outcome in childhood acute lymphoblastic leukemia. Int J Hematol. 2007; 86:166-173.

     [Crossref] [Google Scholar] [PubMed]

417. Dalziel M, Dall'Olio F, Mungul A, Piller V, Piller F. Ras oncogene induces β‐galactoside α2, 6‐sialyltransferase (ST6Gal I) via a RalGEF‐mediated signal to its housekeeping promoter. Eur J Biochem. 2004;271(18):3623-3634. 

     [Crossref] [Google Scholar] [PubMed]

418. Abdul-Ghani R, Serra V, Györffy B, Jürchott K, Solf A, Dietel M, et al. The PI3K inhibitor LY294002 blocks drug export from resistant colon carcinoma cells overexpressing MRP1. Oncogene. 2006;25(12):1743-1752. 

     [Crossref] [Google Scholar] [PubMed]

419. Tazzari PL, Cappellini A, Ricci F, Evangelisti C, Papa V, Grafone T, et al. Multidrug resistance-associated protein 1 expression is under the control of the phosphoinositide 3 kinase/Akt signal transduction network in human acute myelogenous leukemia blasts. Leukemia. 2007;21(3):427-438. 

     [Crossref] [Google Scholar] [PubMed]

420. Thomas X. Profile of inotuzumab ozogamicin and its potential in the treatment of acute lymphoblastic leukemia. Blood Lymphatic Cancer: Targets and Therapy. 2014:1-8.

     [Google Scholar]

421. Lu JF, Pokharel D, Bebawy M. MRP1 and its role in anticancer drug resistance. Drug Metab Rev. 2015;47(4):406-419.

     [Crossref] [Google Scholar] [PubMed]

422. Ma H, Cheng L, Hao K, Li Y, Song X, Zhou H, et al. Reversal effect of ST6GAL 1 on multidrug resistance in human leukemia by regulating the PI3K/Akt pathway and the expression of P-gp and MRP1. PLoS One. 2014;9(1): e85113.

     [Crossref] [Google Scholar] [PubMed]

423. Chang LY, Liang SY, Lu SC, Tseng HC, Tsai HY, Tang CJ, et al. Molecular basis and role of Siglec-7 ligand expression on chronic lymphocytic leukemia B cells. Front Immunol. 2022;13: 840388.

     [Crossref] [Google Scholar] [PubMed]

424. Zhou H, Li Y, Liu B, Shan Y, Li Y, Zhao L, et al. Downregulation of miR-224 and let-7i contribute to cell survival and chemoresistance in chronic myeloid leukemia cells by regulating ST3GAL IV expression. Gene. 2017; 626:106-118.

     [Crossref] [Google Scholar] [PubMed]

425. Glavey S, Wu P, Murillo LS, Loughrey C, Roccaro AM, Morgan GJ, et al. Low expression of the FUCA1 gene is an adverse prognostic factor in myeloma and combined with high sialyltransferase gene expression identifies patients at increased risk of early disease progression and death. Blood. 2013;122(21):1864.

     [Crossref] [Google Scholar]

426. Taniguchi N, Miyoshi E, Ko JH, Ikeda Y, Ihara Y. Implication of N-acetylglucosaminyltransferases III and V in cancer: Gene regulation and signaling mechanism. Biochim Biophys Acta. 1999;1455(2-3):287-300.

     [Crossref] [Google Scholar] [PubMed]

427. Blöchl C, Wang D, Mayboroda OA, Lageveen-Kammeijer GS, Wuhrer M. Transcriptionally imprinted glycomic signatures of acute myeloid leukemia. Cell Biosci. 2023;13(1):31.

     [Crossref] [Google Scholar] [PubMed]

428. Zhang X, Dong W, Zhou H, Li H, Wang N, Miao X, et l. α‐2, 8‐sialyltransferase is involved in the development of multidrug resistance via PI 3 K/A kt pathway in human chronic myeloid leukemia. IUBMB Life. 2015;67(2):77-87.

     [Crossref] [Google Scholar] [PubMed]

429. Takashima S, Ishida HK, Inazu T, Ando T, Ishida H, Kiso M, et al. Molecular cloning and expression of a sixth type of α2, 8-sialyltransferase (st8sia vi) that sialylatesO-glycans. J Biol Chem. 2002;277(27):24030-24038.

     [Crossref] [Google Scholar] [PubMed]

430. Ma H, Zhou H, Song X, Shi S, Zhang J, Jia L. Modification of sialylation is associated with multidrug resistance in human acute myeloid leukemia. Oncogene. 2015 Feb;34(6):726-740.

     [Crossref] [Google Scholar] [PubMed]

431. Glavey SV, Manier S, Natoni A, Sacco A, Moschetta M, Reagan MR, et al. The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma. Blood. 2014;124(11):1765-1776.

     [Crossref] [Google Scholar] [PubMed]

432. Yamada K, Mitsui Y, Kakoi N, Kinoshita M, Hayakawa T, Kakehi K. One-pot characterization of cancer cells by the analysis of mucin-type glycans and glycosaminoglycans. Anal Biochem. 2012;421(2):595-606.

     [Crossref] [Google Scholar] [PubMed]

433. Yamashiro S, Okada M, Haraguchi M, Furukawa K, Lloyd KO, Shiku H, et al. Expression of α2, 8-sialyltransferase (GD3 synthase) gene in human cancer cell lines: High level expression in melanomas and up-regulation in activated T lymphocytes. Glycoconj J. 1995; 12:894-900.

     [Crossref] [Google Scholar] [PubMed]

434. Mondal S, Chandra S, Mandal C. Elevated mRNA level of hST6Gal I and hST3Gal V positively correlates with the high risk of pediatric acute leukemia. Leuk Res. 2010;34(4):463-470.

     [Crossref] [Google Scholar] [PubMed]

435. Martersteck CM, Kedersha NL, Drapp DA, Tsui TG, Colley KJ. Unique α2, 8-polysialylated glycoproteins in breast cancer and leukemia cells. Glycobiology. 1996;6(3):289-301.

     [Crossref] [Google Scholar] [PubMed]

436. ST3GAL3. ST3 beta-galactoside alpha-2,3-sialyltransferase 3. Human Protein Atlas. 2024.
437. Figueroa ME, Skrabanek L, Li Y, Jiemjit A, Fandy TE, Paietta E, et al. MDS and secondary AML display unique patterns and abundance of aberrant DNA methylation. Blood. 2009;114(16):3448-3458.

     [Crossref] [Google Scholar] [PubMed]

438. Zhou X, Yang G, Guan F. Biological functions and analytical strategies of sialic acids in tumor. Cells. 2020;9(2):273.

     [Crossref] [Google Scholar] [PubMed]

439. Kannagi R, Sakuma K, Miyazaki K, Lim KT, Yusa A, Yin J, et al. Altered expression of glycan genes in cancers induced by epigenetic silencing and tumor hypoxia: Clues in the ongoing search for new tumor markers. Cancer Sci. 2010;101(3):586-593.

     [Crossref] [Google Scholar] [PubMed]

440. Fedarko NS, Fohr B, Robey PG, Young MF, Fisher LW. Factor H binding to bone sialoprotein and osteopontin enables tumor cell evasion of complement-mediated attack. J Biol Chem. 2000;275(22):16666-16672.

     [Crossref] [Google Scholar] [PubMed]

441. Giles JR, Globig AM, Kaech SM, Wherry EJ. CD8+ T cells in the cancer-immunity cycle. Immunity. 2023;56(10):2231-2253.

     [Crossref] [Google Scholar] [PubMed]

442. Boelaars K, Goossens-Kruijssen L, Wang D, de Winde CM, Rodriguez E, Lindijer D, et al. Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer. J Immunother Cancer. 2023;11(11).

     [Crossref] [Google Scholar] [PubMed]

443. McEver RP. Selectins: Initiators of leucocyte adhesion and signalling at the vascular wall. Cardiovasc Res. 2015;107(3):331-339.

     [Crossref] [Google Scholar] [PubMed]

444. Fukuoka K, Narita N, Saijo N. Increased expression of sialyl Lewisx antigen is associated with distant metastasis in lung cancer patients: Immunohistochemical study on bronchofiberscopic biopsy specimens. Lung Cancer. 1998;20(2):109-116. 

     [Crossref] [Google Scholar] [PubMed]

445. Tatsumi M, Watanabe A, Sawada H, Yamada Y, Shino Y, Nakano H. Immunohistochemical expression of the sialyl Lewis x antigen on gastric cancer cells correlates with the presence of liver metastasis. Clin Exp Metastasis. 1998; 16:743-750.

     [Crossref] [Google Scholar] [PubMed]

446. Ben-David T, Sagi-Assif O, Meshel T, Lifshitz V, Yron I, Witz IP. The involvement of the sLe-a selectin ligand in the extravasation of human colorectal carcinoma cells. Immunol Lett. 2008;116(2):218-224.

     [Crossref] [Google Scholar] [PubMed]

447. Geng Y, Yeh K, Takatani T, King MR. Three to tango: MUC1 as a ligand for both E-selectin and ICAM-1 in the breast cancer metastatic cascade. Front Oncol. 2012 ;2:76.

     [Crossref] [Google Scholar] [PubMed]

448. Li J, Guillebon AD, Hsu JW, Barthel SR, Dimitroff CJ, Lee YF, et al. Human fucosyltransferase 6 enables prostate cancer metastasis to bone. Br J Cancer. 2013;109(12):3014-3022.

     [Crossref] [Google Scholar] [PubMed]

449. Martinez-Moreno M, Leiva M, Aguilera-Montilla N, Sevilla-Movilla S, Isern de Val S, Arellano-Sanchez N, et al. In vivo adhesion of malignant B cells to bone marrow microvasculature is regulated by α4β1 cytoplasmic-binding proteins. Leukemia. 2016;30(4):861-872.

     [Crossref] [Google Scholar] [PubMed]

450. Garcia-Ortiz A, Rodríguez-García Y, Encinas J, Maroto-Martín E, Castellano E, Teixidó J, et al. The role of tumor microenvironment in multiple myeloma development and progression. Cancers. 2021;13(2):217.

     [Crossref] [Google Scholar] [PubMed]

451. Natoni A, Farrell ML, Harris S, Falank C, Kirkham-McCarthy L, Macauley MS, et al. Sialyltransferase inhibition leads to inhibition of tumor cell interactions with E-selectin, VCAM1, and MADCAM1, and improves survival in a human multiple myeloma mouse model. Haematologica. 2019;105(2):457.

     [Crossref] [Google Scholar] [PubMed]

452. Kim I, Uchiyama H, Chauhan D, Anderson KC. Cell surface expression and functional significance of adhesion molecules on human myeloma‐derived cell lines. Br J Haematol. 1994;87(3):483-493.

     [Crossref] [Google Scholar] [PubMed]

453. Tatsumi T, Shimazaki C, Goto H, Araki SI, Sudo Y, Yamagata N, et al. Expression of adhesion molecules on myeloma cells. Jpn J Cancer Res. 1996;87(8):837-842.

     [Crossref] [Google Scholar] [PubMed]

454. Neri P, Ren L, Azab AK, Brentnall M, Gratton K, Klimowicz AC, et al. Integrin β7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion. Blood. 2011;117(23):6202-6213.

     [Crossref] [Google Scholar] [PubMed]

455. Natoni A, Bohara R, Pandit A, O'Dwyer M. Targeted approaches to inhibit sialylation of multiple myeloma in the bone marrow microenvironment. Front Bioeng Biotechnol. 2019;7:252.

     [Crossref] [Google Scholar] [PubMed]

456. D’Addio M, Frey J, Otto VI. The manifold roles of sialic acid for the biological functions of endothelial glycoproteins. Glycobiology. 2020;30(8):490-499.

     [Crossref] [Google Scholar] [PubMed]

457. Schauer R. Sialic acids as regulators of molecular and cellular interactions. Curr Opin Struct Biol. 2009;19(5):507-514.

     [Crossref] [Google Scholar] [PubMed]

458. Irie A, Koyama S, Kozutsumi Y, Kawasaki T, Suzuki A. The molecular basis for the absence ofN-glycolylneuraminic acid in humans. J Biol Chem. 1998;273(25):15866-15871.

     [Crossref] [Google Scholar] [PubMed]

459. Varki A. N-glycolylneuraminic acid deficiency in humans. Biochimie. 2001;83(7):615-622.

     [Crossref] [Google Scholar] [PubMed]

460. Samraj AN, Läubli H, Varki N, Varki A. Involvement of a non-human sialic acid in human cancer. Front Oncol. 2014;4:33.

     [Crossref] [Google Scholar] [PubMed]

461. Hedlund M, Tangvoranuntakul P, Takematsu H, Long JM, Housley GD, Kozutsumi Y, et al. N-glycolylneuraminic acid deficiency in mice: Implications for human biology and evolution. Mol Cell Biol. 2007;27(12):4340-4346.

     [Crossref] [Google Scholar] [PubMed]

462. Yin J, Hashimoto A, Izawa M, Miyazaki K, Chen GY, Takematsu H, et al. Hypoxic culture induces expression of sialin, a sialic acid transporter, and cancer-associated gangliosides containing non-human sialic acid on human cancer cells. Cancer Res. 2006;66(6):2937-2945.

     [Crossref] [Google Scholar] [PubMed]

463. Yin J, Miyazaki K, Shaner RL, Merrill Jr AH, Kannagi R. Altere    d sphingolipid metabolism induced by tumor hypoxia-new vistas in glycolipid tumor markers. FEBSLett. 2010;584(9):1872-1878.

     [Crossref] [Google Scholar] [PubMed]

464. Pearce OM, Läubli H. Sialic acids in cancer biology and immunity. Glycobiology. 2016;26(2):111-128.

     [Crossref] [Google Scholar] [PubMed]

465. Fernández-Marrero Y, Hernández T, Roque-Navarro L, Talavera A, Moreno E, Griñán T, et al. Switching on cytotoxicity by a single mutation at the heavy chain variable region of an anti-ganglioside antibody. Mol Immunol. 2011;48(8):1059-1067.

     [Crossref] [Google Scholar] [PubMed]

466. Moloney DJ, Shair LH, Lu FM, Xia J, Locke R, Matta KL, et al. Mammalian Notch1 is modified with two unusual forms ofO-linked glycosylation found on epidermal growth factor-like modules. J Biol Chem. 2000;275(13):9604-9011.

     [Crossref] [Google Scholar] [PubMed]

467. Xiu MX, Liu YM, Kuang BH. The role of DLLs in cancer: A novel therapeutic target. Onco Targets Ther. 2020:3881-3901.

     [Crossref] [Google Scholar] [PubMed]

468. Platonova N, Lesma E, Basile A, Bignotto M, Garavelli S, Teresa Palano M, et al. Targeting Notch as a therapeutic approach for human malignancies. Curr Pharm Des. 2017;23(1):108-134. 

     [Crossref] [Google Scholar] [PubMed]

469. Pinho SS, Reis CA. Glycosylation in cancer: Mechanisms and clinical implications. Nat Rev Cancer. 2015;15(9):540-555.

     [Crossref] [Google Scholar] [PubMed]

470. Wang MM. Notch signaling and notch signaling modifiers. Int J Biochem Cell Biol. 2011;43(11):1550-1562.

     [Crossref] [Google Scholar] [PubMed]

471. Dexter JS. The analysis of a case of continuous variation in drosophila by a study of its linkage relations. Am Nat. 1914;48(576):712-758.

     [Crossref] [Google Scholar]

472. Saiki W, Ma C, Okajima T, Takeuchi H. Current views on the roles of O-glycosylation in controlling notch-ligand interactions. Biomolecules. 2021;11(2):309.

     [Crossref] [Google Scholar] [PubMed]

473. Siebel C, Lendahl U. Notch signaling in development, tissue homeostasis, and disease. Physiol Rev. 2017;97(4):1235-1294.

     [Crossref] [Google Scholar] [PubMed]

474. Bray SJ. Notch signalling in context. Nat Rev Mol Cell Biol. 2016;17(11):722-735.

     [Crossref] [Google Scholar] [PubMed]

475. Meurette O, Mehlen P. Notch signaling in the tumor microenvironment. Cancer Cell. 2018;34(4):536-548.

     [Crossref] [Google Scholar] [PubMed]

476. Haltom AR, Jafar-Nejad H. The multiple roles of epidermal growth factor repeat O-glycans in animal development. Glycobiology. 2015;25(10):1027-1042.

     [Crossref] [Google Scholar] [PubMed]

477. Kopan R, Ilagan MX. The canonical notch signaling pathway: Unfolding the activation mechanism. Cell. 2009;137(2):216-233.

     [Crossref] [Google Scholar] [PubMed]

478. Andersson ER, Sandberg R, Lendahl U. Notch signaling: Simplicity in design, versatility in function. Development. 2011;138(17):3593-3612.

     [Crossref][Google Scholar][PubMed]

479. Boerkoel P, Huynh S, Yang GX, Boerkoel CF, Patel MS, Lehman A, et al. NOTCH1 loss of the TAD and PEST domain: An antimorph? Am J Med Genet A. 2023;191(6):1593-1598.

     [Crossref][Google Scholar][PubMed]

480. Kurooka H, Kuroda K, Honjo T. Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region. Nucleic Acids Res. 1998;26(23):5448-5455.

     [Crossref][Google Scholar][PubMed]

481. Kurooka H, Honjo T. Functional interaction between the mouse notch1 intracellular region and histone acetyltransferases PCAF and GCN5. J Biol Chem. 2000;275(22):17211-17220.

     [Crossref][Google Scholar][PubMed]

482. Gerhardt DM, Pajcini KV, D’altri T, Tu L, Jain R, Xu L, et al. The Notch1 transcriptional activation domain is required for development and reveals a novel role for Notch1 signaling in fetal hematopoietic stem cells. Genes Dev. 2014;28(6):576-593.

     [Crossref][Google Scholar][PubMed]

483. Radtke F, Raj K. The role of Notch in tumorigenesis: Oncogene or tumour suppressor? Nat Rev Cancer. 2003 ;3(10):756-767. 

     [Crossref][Google Scholar][PubMed]

484. Chillakuri CR, Sheppard D, Lea SM, Handford PA. Notch receptor-ligand binding and activation: Insights from molecular studies. Semin Cell Dev Biol. 2012; 23(4):421-428.

     [Crossref][Google Scholar][PubMed]

485. Stanley P, Okajima T. Roles of glycosylation in notch signaling. Curr Top Dev Biol. 2010; 92:131-164.

     [Crossref][Google Scholar][PubMed]

486. Haines N, Irvine KD. Glycosylation regulates notch signalling. Nat Rev Mol Cell Biol. 2003; 4(10):786-797.

     [Crossref] [Google Scholar] [PubMed]

487. Stanley P. Regulation of notch signaling by glycosylation. Curr Opin Struct Biol. 2007;17(5):530-535.

     [Crossref] [Google Scholar] [PubMed]

488. Takeuchi H, Haltiwanger RS. Role of glycosylation of notch in development. Semin Cell Dev Biol. 2010;21(6):638-645.

     [Crossref] [Google Scholar] [PubMed]

489. Takeuchi H, Haltiwanger RS. Significance of glycosylation in notch signaling. Biochem Biophys Res Commun. 2014;453(2):235-242.

     [Crossref] [Google Scholar] [PubMed]

490. Takeuchi H, Fernández Valdivia RC, Caswell DS, Nita Lazar A, Rana NA, Garner TP, et al. Rumi functions as both a protein O-glucosyltransferase and a protein O-xylosyltransferase. Proc Natl Acad Sci USA. 2011;108(40):16600-16605.

     [Crossref] [Google Scholar] [PubMed]

491. Pakkiriswami S, Couto A, Nagarajan U, Georgiou M. Glycosylated notch and cancer. Front Oncol. 2016; 6:37.

     [Crossref] [Google Scholar] [PubMed]

492. Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC. Structural basis for Notch1 engagement of Delta-like 4. Science. 2015;347(6224):847-853.

     [Crossref] [Google Scholar] [PubMed]

493. Luca VC, Kim BC, Ge C, Kakuda S, Wu D, Roein-Peikar M, et al. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science. 2017;355(6331):1320-1324.

     [Crossref] [Google Scholar] [PubMed]

494. Kakuda S, Haltiwanger RS. Deciphering the fringe-mediated notch code: Identification of activating and inhibiting sites allowing discrimination between ligands. Dev Cell. 2017;40(2):193-201.

     [Crossref] [Google Scholar] [PubMed]

495. Moloney DJ, Shair LH, Lu FM, Xia J, Locke R, Matta KL, et al. Mammalian notch1 is modified with two unusual forms of O-linked glycosylation found on epidermal growth factor-like modules. J Biol Chem. 2000;275(13):9604-9611.

     [Crossref] [Google Scholar] [PubMed]

496. Brückner K, Perez L, Clausen H, Cohen S. Glycosyltransferase activity of fringe modulates notch-delta interactions. Nature. 2000;406(6794):411-415.

     [Crossref] [Google Scholar] [PubMed]

497. Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, et al. Fringe is a glycosyltransferase that modifies Notch. Nature. 2000;406(6794):369-375. 

     [Crossref] [Google Scholar] [PubMed]

498. Sasamura T, Ishikawa HO, Sasaki N, Higashi S, Kanai M, Nakao S, et al. The O-fucosyltransferase O-fut1 is an extracellular component that is essential for the constitutive endocytic trafficking of notch in drosophila. Development. 2007;134(7):1347-1356

     [Crossref] [Google Scholar] [PubMed]

499. Luo Y, Haltiwanger RS. O-fucosylation of notch occurs in the endoplasmic reticulum. J Biol Chem. 2005;280(12):11289-11294.

     [Crossref] [Google Scholar] [PubMed]

500. Shi S, Stanley P. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. Proc Natl Acad Sci USA. 2003;100(9):5234-5239.

     [Crossref] [Google Scholar] [PubMed]

501. Okajima T, Irvine KD. Regulation of notch signaling by o-linked fucose. Cell. 2002;111(6):893-904.

     [Crossref] [Google Scholar] [PubMed]

502. Brückner K, Perez L, Clausen H, Cohen S. Glycosyltransferase activity of fringe modulates notch-delta interactions. Nature. 2000;406(6794):411-415.

     [Crossref] [Google Scholar] [PubMed]

503. Munro S, Freeman M. The notch signalling regulator fringe acts in the golgi apparatus and requires the glycosyltransferase signature motif DXD. Curr Biol. 2000;10(14):813-820.

     [Crossref] [Google Scholar] [PubMed]

504. Ishio A, Sasamura T, Ayukawa T, Kuroda J, Ishikawa HO, Aoyama N, et al. O-fucose monosaccharide of drosophila notch has a temperature-sensitive function and cooperates with O-glucose glycan in notch transport and notch signaling activation. J Biol Chem. 2015;290(1):505-519.

     [Crossref] [Google Scholar] [PubMed]

505. Moloney DJ, Shair LH, Lu FM, Xia J, Locke R, Matta KL, et al. Mammalian notch1 is modified with two unusual forms of o-linked glycosylation found on epidermal growth factor-like modules. J Biol Chem. 2000;275(13):9604-9611.

     [Crossref] [Google Scholar] [PubMed]

506. Lee TV, Sethi MK, Leonardi J, Rana NA, Buettner FF, Haltiwanger RS, et al. Negative regulation of notch signaling by xylose. PLoS Genet. 2013;9(6): e1003547.

     [Crossref] [Google Scholar] [PubMed]

507. Sethi MK, Buettner FF, Krylov VB, Takeuchi H, Nifantiev NE, Haltiwanger RS, et al. Identification of glycosyltransferase 8 family members as xylosyltransferases acting on O-glucosylated notch epidermal growth factor repeats. J Biol Chem. 2010;285(3):1582-1586.

     [Crossref] [Google Scholar] [PubMed]

508. Sethi MK, Buettner FF, Ashikov A, Krylov VB, Takeuchi H, Nifantiev NE, et al. Molecular cloning of a xylosyltransferase that transfers the second xylose to O-glucosylated epidermal growth factor repeats of notch. J Biol Chem. 2012;287(4):2739-2748.

     [Crossref] [Google Scholar] [PubMed]

509. Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, et al. Rumi is a CAP10 domain glycosyltransferase that modifies notch and is required for notch signaling.Cell.2008;132(2):247-258. 

     [Crossref] [Google Scholar] [PubMed]

510. Fernandez Valdivia R, Takeuchi H, Samarghandi A, Lopez M, Leonardi J, Haltiwanger RS, et al. Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase rumi. Development. 2011;138(10):1925-1934.

     [Crossref] [Google Scholar] [PubMed]]

511. Teng Y, Liu Q, Ma J, Liu F, Han Z, Wang Y, et al. Cloning, expression and characterization of a novel human CAP10-like gene hCLP46 from CD34+ stem/progenitor cells. Gene. 2006;371(1):7-15.

     [Crossref] [Google Scholar] [PubMed]

512. Wang Y, Chang N, Zhang T, Liu H, Ma W, Chu Q, et al. Overexpression of human CAP10-like protein 46 KD in T-acute lymphoblastic leukemia and acute myelogenous leukemia. Genet Test Mol Biomarkers. 2010;14(1):127-133.

     [Crossref] [Google Scholar] [PubMed]

513. Matsuura A, Ito M, Sakaidani Y, Kondo T, Murakami K, Furukawa K, et al. O-linked N-acetylglucosamine is present on the extracellular domain of notch receptors. J Biol Chem. 2008;283(51):35486-35495.

     [Crossref] [Google Scholar] [PubMed]

514. Müller R, Jenny A, Stanley P. The EGF repeat-specific O-GlcNAc-transferase Eogt interacts with notch signaling and pyrimidine metabolism pathways in drosophila. PLoS One. 2013;8(5): e62835.

     [Crossref] [Google Scholar] [PubMed]

515. Dominguez M. Oncogenic programmes and notch activity: an ‘organized crime’? Semin Cell Dev Biol. 2014; 28:78-85.

     [Crossref] [Google Scholar] [PubMed]

516. Horne GA, Copland M. Approaches for targeting self-renewal pathways in cancer stem cells: Implications for hematological treatments. Expert Opin Drug Discov. 2017;12(5):465-474.

     [Crossref] [Google Scholar] [PubMed

517. Weng AP, Ferrando AA, Lee W, Morris IV JP, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269-271.

     [Crossref] [Google Scholar] [PubMed]

518. Malyukova A, Dohda T, von der Lehr N, Akhondi S, Corcoran M, Heyman M, et al. The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. Cancer research. 2007;67(12):5611-5616.

     [Crossref] [Google Scholar] [PubMed

519. Klinakis A, Lobry C, Abdel-Wahab O, Oh P, Haeno H, Buonamici S, et al. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature. 2011;473(7346):230-233. 

     [Crossref] [Google Scholar] [PubMed]

520. Lobry C, Ntziachristos P, Ndiaye-Lobry D, Oh P, Cimmino L, Zhu N, et al. Notch pathway activation targets AML-initiating cell homeostasis and differentiation. J Exp Med. 2013;210(2):301-319.

     [Crossref] [Google Scholar] [PubMed]

521. Parmigiani E, Taylor V, Giachino C. Oncogenic and tumor-suppressive functions of NOTCH signaling in glioma. Cells. 2020;9(10):2304.

     [Crossref] [Google Scholar] [PubMed]

522. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem. 2004;279(4):2937-2944.

     [Crossref] [Google Scholar] [PubMed]

523. Nwabo Kamdje AH, Mosna F, Bifari F, Lisi V, Bassi G, Malpeli G, et al. Notch-3 and notch-4 signaling rescue from apoptosis human B-ALL cells in contact with human bone marrow–derived mesenchymal stromal cells. Blood. 2011;118(2):380-389.

     [Crossref] [Google Scholar] [PubMed]

524. Nwabo Kamdje AH, Bassi G, Pacelli L, Malpeli G, Amati E, Nichele I, et al. Role of stromal cell-mediated Notch signaling in CLL resistance to chemotherapy. Blood Cancer J. 2012;2(5): e73.

     [Crossref] [Google Scholar] [PubMed]

525. Kamga PT, Bassi G, Cassaro A, Midolo M, Di Trapani M, Gatti A, et al. Notch signalling drives bone marrow stromal cell-mediated chemoresistance in acute myeloid leukemia. Oncotarget. 2016;7(16):21713.

     [Crossref] [Google Scholar] [PubMed]

526. Jundt F, Anagnostopoulos I, Förster R, Mathas S, Stein H, Dörken B. Activated notch1 signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002;99(9):3398-3403.

     [Crossref] [Google Scholar] [PubMed]

527. Ding Y, Shen Y. Notch increased vitronection adhesion protects myeloma cells from drug induced apoptosis. Biochem Biophys Res Commun. 2015;467(4):717-722.

     [Crossref] [Google Scholar] [PubMed]

528. Garavelli S, Lazzari E, Colombo M, Platonova N, Palano MT, Baccianti F, et al. The role of notch pathway in multiple myeloma associated drug resistance. Cancer Res. 2017;1538-7445  

     [Google Scholar]

529. Colombo M, Platonova N, Giannandrea D, Palano MT, Basile A, Chiaramonte R. Re-establishing apoptosis competence in bone associated cancers viacommunicative reprogramming induced through notch signaling inhibition. Front Pharmacol. 2019; 10:145.

     [Crossref] [Google Scholar] [PubMed]

530. Colombo M, Mirandola L, Platonova N, Apicella L, Basile A, Figueroa AJ, et al. Notch-directed microenvironment reprogramming in myeloma: a single path to multiple outcomes. Leukemia. 2013;27(5):1009-1018.

     [Crossref] [Google Scholar] [PubMed]

531. Škrtić A, Korać P, Krišto DR, Stojisavljević RA, Ivanković D, Dominis M. Immunohistochemical analysis of NOTCH1 and JAGGED1 expression in multiple myeloma and monoclonal gammopathy of undetermined significance. Hum Pathol. 2010;41(12):1702-1710.

     [Crossref] [Google Scholar] [PubMed]

532. Colombo M, Galletti S, Bulfamante G, Falleni M, Tosi D, Todoerti K, et al. Multiple myeloma-derived jagged ligands increases autocrine and paracrine interleukin-6 expression in bone marrow niche. Oncotarget. 2016;7(35):56013.

     [Crossref] [Google Scholar] [PubMed]

533. Mundy GR. Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584-593.

     [Crossref] [Google Scholar] [PubMed]

534. Delgado-Calle J, Anderson J, Cregor MD, Hiasa M, Chirgwin JM, Carlesso N, et al. Bidirectional notch signaling and osteocyte-derived factors in the bone marrow microenvironment promote tumor cell proliferation and bone destruction in multiple myeloma. Cancer Res. 2016;76(5):1089-1100.

     [Crossref] [Google Scholar] [PubMed]

535. Colombo M, Thümmler K, Mirandola L, Garavelli S, Todoerti K, Apicella L, et al. Notch signaling drives multiple myeloma induced osteoclastogenesis. Oncotarget. 2014;5(21):10393.

     [Crossref] [Google Scholar] [PubMed]

536. Mirandola L, Apicella L, Colombo M, Yu Y, Berta DG, Platonova N, et al. Anti-Notch treatment prevents multiple myeloma cells localization to the bone marrow via the chemokine system CXCR4/SDF-1. Leukemia. 2013;27(7):1558-1566.

     [Crossref] [Google Scholar] [PubMed]

537. Takeuchi T, Adachi Y, Ohtsuki Y. Skeletrophin, a novel ubiquitin ligase to the intracellular region of Jagged-2, is aberrantly expressed in multiple myeloma. Am J Pathol. 2005;166(6):1817-1826.

     [Crossref] [Google Scholar] [PubMed]

538. Colombo M, Galletti S, Garavelli S, Platonova N, Paoli A, Basile A, et al. Notch signaling deregulation in multiple myeloma: A rational molecular target. Oncotarget. 2015;6(29):26826.

     [Crossref] [Google Scholar] [PubMed]

539. Jundt F, Pröbsting KS, Anagnostopoulos I, Muehlinghaus G, Chatterjee M, Mathas S, et al. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 2004;103(9):3511-3515.

     [Crossref] [Google Scholar] [PubMed]

540. Pisklakova A, Grigson E, Ozerova M, Chen F, Sullivan DM, Nefedova Y. Anti-myeloma effect of pharmacological inhibition of Notch/gamma-secretase with RO4929097 is mediated by modulation of tumor microenvironment. Cancer Biol Ther. 2016;17(5):477-85.

     [Crossref] [Google Scholar] [PubMed]

541. Schwarzer R, Nickel N, Godau J, Willie BM, Duda GN, Cirovic B, et al. Notch pathway inhibition controls myeloma bone disease in the murine MOPC315. BM model. Blood Cancer J. 2014;4(6): e217.

     [Crossref] [Google Scholar] [PubMed]

542. Ramakrishnan V, Ansell S, Haug J, Grote D, Kimlinger T, Stenson M, et al. MRK003, a γ-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma. Leukemia. 2012;26(2):340-348.

     [Crossref] [Google Scholar] [PubMed]

543. Zweidler McKay PA, He Y, Xu L, Rodriguez CG, Karnell FG, Carpenter AC, et al. Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood. 2005;106(12):3898-3906.

     [Crossref] [Google Scholar] [PubMed]

544. Xu D, Hu J, De Bruyne E, Menu E, Schots R, Vanderkerken K, et al. Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma. biochemical and biophysical research communications. 2012;428(4):518-524.

     [Crossref] [Google Scholar] [PubMed]

545. Xu D, Hu J, Xu S, De Bruyne E, Menu E, Van Camp B, et al. Dll1/Notch activation accelerates multiple myeloma disease development by promoting CD138+ MM-cell proliferation. Leukemia. 2012;26(6):1402-1405.

     [Crossref] [Google Scholar] [PubMed]

546. Sabol HM, Ferrari AJ, Adhikari M, Amorim T, McAndrews K, Anderson J, et al. Targeting notch inhibitors to the myeloma bone marrow niche decreases tumor growth and bone destruction without gut toxicity. Cancer Res. 2021;81(19):5102-5114.

     [Crossref] [Google Scholar] [PubMed]

547. Gau YC, Yeh TJ, Hsu CM, Hsiao SY, Hsiao HH. Pathogenesis and treatment of myeloma-related bone disease. Int J Mol Sci. 2022;23(6):3112.

     [Crossref] [Google Scholar] [PubMed]

548. Li M, Chen F, Clifton N, Sullivan DM, Dalton WS, Gabrilovich DI, et al. Combined inhibition of notch signaling and Bcl-2/Bcl-xL results in synergistic antimyeloma effect. Mol Cancer Ther. 2010;9(12):3200-3209.

     [Crossref] [Google Scholar] [PubMed]

549. Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI. Inhibition of notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 2008;111(4):2220-2229.

     [Crossref] [Google Scholar] [PubMed]

550. Campagnari A, Belver L. NOTCH1-Induced T-Cell acute lymphoblastic leukemia in vivo models. Methods Mol Biol.2024:2773:9-24.

     [Crossref] [Google Scholar] [PubMed]

551. Breit S, Stanulla M, Flohr T, Schrappe M, Ludwig WD, Tolle G, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood. 2006;108(4):1151-1157.

     [Crossref] [Google Scholar] [PubMed]

552. Ferrando AA. The role of NOTCH1 signaling in T-ALL. Hematol Am Soc Hematol Educ Program. 2009;2009(1):353-361.

     [Crossref] [Google Scholar] [PubMed]

553. Rossi D, Rasi S, Fabbri G, Spina V, Fangazio M, Forconi F, et al. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia. Blood. 2012;119(2):521-529.

     [Crossref] [Google Scholar] [PubMed]

554. Puente XS, Pinyol M, Quesada V, Conde L, Ordóñez GR, Villamor N, et al. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature. 2011;475(7354):101-105.

     [Crossref] [Google Scholar] [PubMed]

555. Di Ianni M, Baldoni S, Rosati E, Ciurnelli R, Cavalli L, Martelli MF, et al. A new genetic lesion in B‐CLL: a NOTCH1 PEST domain mutation. Br J Haematol. 2009;146(6):689-691.

     [Crossref] [Google Scholar] [PubMed]

556. Fabbri G, Rasi S, Rossi D, Trifonov V, Khiabanian H, Ma J, et al. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation. J Exp Med. 2011;208(7):1389-1401.

     [Crossref] [Google Scholar] [PubMed]

557. Nadeu F, Delgado J, Royo C, Baumann T, Stankovic T, Pinyol M, et al. Clinical impact of clonal and subclonal TP53, SF3B1, BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia. Blood. 2016;127(17):2122-2130.

     [Crossref] [Google Scholar] [PubMed]

558. Rosati E, Baldoni S, De Falco F, Del Papa B, Dorillo E, Rompietti C, et al. NOTCH1 aberrations in chronic lymphocytic leukemia. Front Oncol. 2018; 8:229.

     [Crossref] [Google Scholar] [PubMed]

559. Lobry C, Oh P, Mansour MR, Look AT, Aifantis I. Notch signaling: Switching an oncogene to a tumor suppressor. Blood. 2014;123(16):2451-2459.

     [Crossref] [Google Scholar] [PubMed]

560. Aref S, Rizk R, El Agder M, Fakhry W, El Zafarany M, Sabry M. NOTCH-1 gene mutations influence survival in acute myeloid leukemia patients. Asian Pac J Cancer Prev. 2020;21:1987-1992.

     [Crossref] [Google Scholar] [PubMed]

561. Láinez González D, Serrano López J, Alonso Dominguez JM. Understanding the notch signaling pathway in acute myeloid leukemia stem cells: from hematopoiesis to neoplasia. Cancers. 2022;14(6):1459.

     [Crossref] [Google Scholar] [PubMed]

562. Le Q, Hadland B, Meshinchi S, Bernstein I. Notch blockade overcomes endothelial cell-mediated resistance of FLT3/ITD-positive AML progenitors to AC220 treatment. Leukemia. 2021;35(2):601-605.

     [Crossref] [Google Scholar] [PubMed]

563. Li D, Li T, Shang Z, Zhao L, Xu Q, Tan J, et al. Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD+ acute myeloid leukemia. Signal Transduct Target Ther. 2020;5(1):21.

     [Crossref] [Google Scholar] [PubMed]

564. Fischer J, Erkner E, Fitzel R, Radszuweit P, Keppeler H, Korkmaz F, et al. Uncovering NOTCH1 as a promising target in the treatment of mll-rearranged leukemia. Int J Mol Sci. 2023;24(19):14466.

     [Crossref] [Google Scholar] [PubMed]

565. Ma W, Du J, Chu Q, Wang Y, Liu L, Song M, et al. hCLP46 regulates U937 cell proliferation via Notch signaling pathway. Biochem Biophys Res Commun. 2011;408(1):84-88.

     [Crossref] [Google Scholar] [PubMed]

566. Yao D, Huang Y, Huang X, Wang W, Yan Q, Wei L. Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of notch receptor ligand interactions. Blood. 2011;117(21):5652-5662.

     [Crossref] [Google Scholar] [PubMed]

567. Chu Q, Liu L, Wang W. Overexpression of hCLP 46 enhances notch activation and regulates cell proliferation in a cell type‐dependent manner. Cell Prolif. 2013;46(3):254-262.

     [Crossref] [Google Scholar] [PubMed]

568. Wang S, Itoh M, Shiratori E, Ohtaka M, Tohda S. NOTCH activation promotes glycosyltransferase expression in human myeloid leukemia cells. Hematol Rep. 2018;10(3):7576.

     [Crossref] [Google Scholar] [PubMed]

569. Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity. 2003;18(5):675-685.

     [Crossref] [Google Scholar] [PubMed]

570. Witt CM, Won WJ, Hurez V, Klug CA. Notch2 haploinsufficiency results in diminished B1 B cells and a severe reduction in marginal zone B cells. J Immunol. 2003;171(6):2783-2788.

     [Crossref] [Google Scholar] [PubMed]

571. Lee SY, Kumano K, Nakazaki K, Sanada M, Matsumoto A, Yamamoto G. Gain‐of‐function mutations and copy number increases of Notch2 in diffuse large B‐cell lymphoma. Cancer Sci. 2009;100(5):920-926.

     [Crossref] [Google Scholar] [PubMed]

572. Kiel MJ, Velusamy T, Betz BL, Zhao L, Weigelin HG, Chiang MY. Whole-genome sequencing identifies recurrent somatic NOTCH2 mutations in splenic marginal zone lymphoma. J Exp Med. 2012;209(9):1553-1565.

     [Crossref] [Google Scholar] [PubMed]

573. Rossi D, Trifonov V, Fangazio M, Bruscaggin A, Rasi S, Spina V, et al. The coding genome of splenic marginal zone lymphoma: Activation of NOTCH2 and other pathways regulating marginal zone development. J Exp Med. 2012;209(9):1537-1551.

     [Crossref] [Google Scholar] [PubMed]

574. Arcaini L, Rossi D, Paulli M. Splenic marginal zone lymphoma: From genetics to management. Blood. 2016;127(17):2072-2081.

     [Crossref] [Google Scholar] [PubMed]

575. Sabol HM, Delgado-Calle J. The multifunctional role of Notch signaling in multiple myeloma. J Cancer Metastasis Treat. 2021;7.

     [Crossref] [Google Scholar] [PubMed]

576. Foley DA, Swartzentruber KG, Colley KJ. Identification of sequences in the polysialyltransferases ST8Sia II and ST8Sia IV that are required for the protein-specific polysialylation of the neural cell adhesion molecule, NCAM. J Biol Chem. 2009;284(23):15505-15516. 

     [Crossref] [Google Scholar] [PubMed]

577. Seki T, Arai Y. Expression of highly polysialylated NCAM in the neocortex and piriform cortex of the developing and the adult rat. Anat Embryol. 1991; 184:395-401.

     [Crossref] [Google Scholar] [PubMed]

578. Li J, Yang R, Yang H, Chen S, Wang L, Li M, et al. NCAM regulates the proliferation, apoptosis, autophagy, EMT, and migration of human melanoma cells via the Src/Akt/mTOR/cofilin signaling pathway. J Cell Biochem. 2020;121(2):1192-1204.

     [Crossref] [Google Scholar] [PubMed]

579. Hauser MA, Kindinger I, Laufer JM, Späte AK, Bucher D, Vanes SL, et al. Distinct CCR7 glycosylation pattern shapes receptor signaling and endocytosis to modulate chemotactic responses. J Leukoc Biol. 2016;99(6):993-1007.

     [Crossref] [Google Scholar] [PubMed]

580. Verhallen L, Lackman JJ, Wendt R, Gustavsson M, Yang Z, Narimatsu Y, et al. “Glyco-sulfo barcodes” regulate chemokine receptor function. Cell Mol Life Sci. 2023;80(2):55.

     [Crossref] [Google Scholar] [PubMed]

581. Yabe U, Sato C, Matsuda T, Kitajima K. Polysialic acid in human milk: CD36 is a new member of mammalian polysialic acid-containing glycoprotein. J Biol Chem. 2003;278(16):13875-13880. 

     [Crossref] [Google Scholar] [PubMed]

582. Werneburg S, Buettner FF, Erben L, Mathews M, Neumann H, Mühlenhoff M, et al. Polysialylation and lipopolysaccharide‐induced shedding of E‐selectin ligand‐1 and neuropilin‐2 by microglia and THP‐1 macrophages. Glia. 2016;64(8):1314-1330. 

     [Crossref] [Google Scholar] [PubMed]

583. Jarahian M, Marofi F, Maashi MS, Ghaebi M, Khezri A, Berger MR. Re-expression of poly/oligo-sialylated adhesion molecules on the surface of tumor cells disrupts their interaction with immune-effector cells and contributes to pathophysiological immune escape. Cancers. 2021;13(20):5203. 

     [Crossref] [Google Scholar] [PubMed]

584. Tanaka F, Otake Y, Nakagawa T, Kawano Y, Miyahara R, Li M, et al. Expression of polysialic acid and STX, a human polysialyltransferase, is correlated with tumor progression in non-small cell lung cancer. Cancer Res. 2000;60(11):3072-3080.

     [Google Scholar] [PubMed]

585. Läubli H, Kawanishi K, George Vazhappilly C, Matar R, Merheb M, Sarwar Siddiqui S. Tools to study and target the siglec-sialic acid axis in cancer. FEBS J. 2021;288(21):6206-6225.

     [Crossref] [Google Scholar] [PubMed]

586. Rodrigues E, Macauley MS. Hypersialylation in cancer: Modulation of inflammation and therapeutic opportunities. Cancers. 2018;10(6):207.

     [Crossref] [Google Scholar] [PubMed]

587. Falconer R, Errington R, Shnyder S, Smith P, Patterson L. Polysialyltransferase: A new target in metastatic cancer. Curr Cancer Drug Targets. 2012;12(8):925-939.

     [Crossref] [Google Scholar] [PubMed]

588. Tanaka F, Otake Y, Nakagawa T, Kawano Y, Miyahara R, Li M, et al. Prognostic significance of polysialic acid expression in resected non-small cell lung cancer. Cancer Res. 2001;61(4):1666-1670.

     [Google Scholar] [PubMed]

589. Al-Saraireh YM, Sutherland M, Springett BR, Freiberger F, Ribeiro Morais G, Loadman PM, et al. Pharmacological inhibition of polysialyltransferase ST8SiaII modulates tumour cell migration. PLoS One. 2013;8(8): e73366. 

     [Crossref] [Google Scholar] [PubMed]

590. Elkashef SM, Allison SJ, Sadiq M, Basheer HA, Ribeiro Morais G, Loadman PM, et al. Polysialic acid sustains cancer cell survival and migratory capacity in a hypoxic environment. Scientific reports. 2016;6(1):33026.

     [Crossref] [Google Scholar] [PubMed]

591. Stanley P, Wuhrer M, Lauc G, Stowell SR, Cummings RD. Structures common to different glycans. 2022.

     [Google Scholar]

592. Zhou D. Why are glycoproteins modified by poly-N-acetyllactosamine glycoconjugates? Curr Protein Pept Sci. 2003;4(1):1-9.

     [Crossref] [Google Scholar] [PubMed]

593. Inaba N, Hiruma T, Togayachi A, Iwasaki H, Wang XH, Furukawa Y, et al. A novel I-branching β-1, 6-N-acetylglucosaminyltransferase involved in human blood group I antigen expression. Blood.2003;101(7):2870-2876.

     [Crossref] [Google Scholar] [PubMed]

594. Zhang H, Meng F, Wu S, Kreike B, Sethi S, Chen W, et al. Engagement of I-branching β-1, 6-N-acetylglucosaminyltransferase 2 in breast cancer metastasis and TGF-β signaling. Cancer Res. 2011;71(14):4846-4856.

     [Crossref] [Google Scholar] [PubMed]

595. Henry S, Oriol R, Samuelson B. Lewis histo-blood group system and associated secretory phenotypes. Vox Sang. 1995;69(3):166-182. 

     [Crossref] [Google Scholar] [PubMed]

596. Kukowska Latallo JF, Larsen RD, Nair RP, Lowe JB. A cloned human cDNA determines expression of a mouse stage-specific embryonic antigen and the Lewis blood group alpha (1, 3/1, 4) fucosyltransferase. Genes Dev. 1990;4(8):1288-1303.

     [Crossref] [Google Scholar] [PubMed]

597. Matsushita Y, Cleary KR, Ota DM, Hoff SD, Irimura T. Sialyl-dimeric lewis-X antigen expressed on mucin-like glycoproteins in colorectal cancer metastases. Lab Invest. 1990;63(6):780-791.

     [Google Scholar] [PubMed]

598. Ritchie DS, Neeson PJ, Khot A, Peinert S, Tai T, Tainton K, et al. Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia. Mol Ther. 2013;21(11):2122-2129.

     [Crossref] [Google Scholar] [PubMed]

599. Costa AF, Senra E, Faria-Ramos I, Teixeira A, Morais J, Pacheco M, et al. ST3GalIV drives SLeX biosynthesis in gastrointestinal cancer cells and associates with cancer cell motility. Glycoconj J. 2023;40(4):421-433.

     [Crossref] [Google Scholar] [PubMed]

600. Nakagoe T, Fukushima K, Tanaka K, Sawai T, Tsuji T, Jibiki M, et al. Evaluation of sialyl Lewis (a), sialyl Lewis (x), and sialyl Tn antigens expression levels as predictors of recurrence after curative surgery in node-negative colorectal cancer patients. J Exp Clin Cancer Res. 2002;21(1):107-113.

     [Google Scholar] [PubMed]

601. Kolben T, Müller L, Meister S, Keilmann L, Buschmann C, Trillsch F, et al. Blood group antigens SLeX, SLeA, and LeY as prognostic markers in endometrial cancer. J Cancer Res Clin Oncol. 2022;148(12):3323-3335.

     [Crossref] [Google Scholar] [PubMed]

602. Takada A, Ohmori K, Takahashi N, Tsuyuoka K, Yago A, Zenita K, et al. Adhesion of human cancer cells to vascular endothelium mediated by a carbohydrate antigen, sialyl Lewis A. Biochem Biophys Res Commun. 1991;179(2):713-719.

     [Crossref] [Google Scholar] [PubMed]

603. Takada A, Ohmori K, Yoneda T, Tsuyuoka K, Hasegawa A, Kiso M, et al. Contribution of carbohydrate antigens sialyl Lewis A and sialyl Lewis X to adhesion of human cancer cells to vascular endothelium. Cancer Res. 1993;53(2):354-361.

     [Crossref] [Google Scholar] [PubMed]

604. Natoni A, Macauley MS, O’Dwyer ME. Targeting selectins and their ligands in cancer. Front Oncol. 2016;6:93.

     [Crossref] [Google Scholar] [PubMed]

605. Cazet A, Julien S, Bobowski M, Burchell J, Delannoy P. Tumour-associated carbohydrate antigens in breast cancer. Breast Cancer Res. 2010;12:1-3.

     [Crossref] [Google Scholar] [PubMed] 

606. Julien S, Ivetic A, Grigoriadis A, QiZe D, Burford B, Sproviero D, et al. Selectin ligand sialyl-Lewis x antigen drives metastasis of hormone-dependent breast cancers. Cancer Res. 2011;71(24):7683-7693.

     [Crossref] [Google Scholar] [PubMed]

607. Yakubenia S, Wild MK. Leukocyte adhesion deficiency II: Advances and open questions. FEBS J. 2006;273(19):4390-4398.

     [Crossref] [Google Scholar] [PubMed]

608. Yakubenia S, Frommhold D, Schölch D, Hellbusch CC, Körner C, Petri B, et al. Leukocyte trafficking in a mouse model for leukocyte adhesion deficiency II/congenital disorder of glycosylation IIc. Blood. 2008;112(4):1472-1481.

     [Crossref] [Google Scholar] [PubMed]

609. Lu L, Varshney S, Yuan Y, Wei HX, Tanwar A, Sundaram S, et al. In vivo evidence for GDP-fucose transport in the absence of transporter SLC35C1 and putative transporter SLC35C2. J Biol Chem. 2023;299(12).

     [Crossref] [Google Scholar] [PubMed]

610. Hollingsworth MA, Swanson BJ. Mucins in cancer: Protection and control of the cell surface. Nat Rev Cancer. 2004;4(1):45-60.

     [Crossref] [Google Scholar] [PubMed]

611. Häuselmann I, Borsig L. Altered tumor-cell glycosylation promotes metastasis. Front Oncol. 2014;4:28.

     [Crossref] [Google Scholar] [PubMed]

612. Läubli H, Borsig L. Selectins promote tumor metastasis. Semin Cancer Biol. 2010;20(3):169-177.

     [Crossref] [Google Scholar] [PubMed]

613. Pimenta DB, Varela VA, Datoguia TS, Caraciolo VB, Lopes GH, Pereira WO. The bone marrow microenvironment mechanisms in acute myeloid leukemia. Front Cell Dev Biol. 2021;9:764698.

     [Crossref] [Google Scholar] [PubMed]

614. Winkler IG, Barbier V, Nowlan B, Jacobsen RN, Forristal CE, Patton JT, et al. Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. Nat Med. 2012;18(11):1651-1657.

     [Crossref] [Google Scholar] [PubMed]

615. Winkler IG, Barbier V, Tay J, Levesque JP, Magnani JL, Fiveash CE, et al. Blocking vascular niche E-selectin dampens AML Stem cell regeneration/survival potential in vivoby inhibiting MAPK/ERK and PI3K/AKT signalling pathways. Blood. 2019;134:2657.

     [Crossref] [Google Scholar] 

616. Erbani J, Tay J, Barbier V, Levesque JP, Winkler IG. Acute myeloid leukemia chemo-resistance is mediated by E-selectin receptor CD162 in bone marrow niches. Front Cell Dev Biol. 2020;8:668.

     [Crossref] [Google Scholar] [PubMed] 

617. Pezeshkian B, Donnelly C, Tamburo K, Geddes T, Madlambayan GJ. Leukemia mediated endothelial cell activation modulates leukemia cell susceptibility to chemotherapy through a positive feedback loop mechanism. PLoS One. 2013;8(4):e60823. x

     [Crossref] [Google Scholar] [PubMed] 

618. Mosteo L, Storer J, Batta K, Searle EJ, Duarte D, Wiseman DH. The dynamic interface between the bone marrow vascular niche and hematopoietic stem cells in myeloid malignancy. Front Cell Dev Biol. 2021;9:635189.

     [Crossref] [Google Scholar] [PubMed]

619. Chien S, Haq SU, Pawlus M, Moon RT, Estey EH, Appelbaum FR, et al. Adhesion of acute myeloid leukemia blasts to E-selectin in the vascular niche enhances their survival by mechanisms such as Wnt activation. Blood. 2013;122(21):61.

     [Crossref] [Google Scholar]

620. Pievani A, Biondi M, Tomasoni C, Biondi A, Serafini M. Location first: Targeting acute myeloid leukemia within its niche. J Clin Med. 2020;9(5):1513.

     [Crossref] [Google Scholar] [PubMed]

621. Chien SS, Dai J, Magnani JL, Sekizaki TS, Fogler WE, Thackray HM, et al. E-selectin ligand expression by leukemic blasts is associated with prognosis in patients with AML. Blood. 2018;132:1513.

     [Crossref] [Google Scholar]

622. Aref S, Salama O, Al-Tonbary Y, Fouda M, Menessy A, El-Sherbiny M. L and E selectins in acute myeloid leukemia: Expression, clinical relevance and relation to patient outcome. Hematology. 2002;7(2):83-87.

     [Crossref] [Google Scholar] [PubMed]

623. Dai Y, Cheng Z, Pang Y, Jiao Y, Qian T, Quan L, et al. Prognostic value of the FUT family in acute myeloid leukemia. Cancer Gene Ther. 2020;27(1):70-80.

     [Crossref] [Google Scholar] [PubMed]

624. Mondal N, Buffone Jr A, Stolfa G, Antonopoulos A, Lau JT, Haslam SM, et al. ST3Gal-4 is the primary sialyltransferase regulating the synthesis of E-, P-, and L-selectin ligands on human myeloid leukocytes. Blood. 2015;125(4):687-696.

     [Crossref] [Google Scholar] [PubMed]

625. Leonti AR, Pardo L, Alonzo TA, Gerbing RB, Brodersen LE, Ries RE, et al. Transcriptome profiling of glycosylation genes defines correlation with E-selectin ligand expression and clinical outcome in AML. Blood. 2019;134:3772.

     [Crossref] [Google Scholar]

626. Blöchl C, Wang D, Madunić K, Lageveen-Kammeijer GS, Huber CG, Wuhrer M, et al. Integrated N-and O-glycomics of Acute Myeloid Leukemia (AML) cell lines. Cells. 2021;10(11):3058.

     [Crossref] [Google Scholar] [PubMed]

627. Enjeti AK, Fogler WE, Smith TA, Lincz LF, Bond DR, Magnani JL. Combining 5‐azacitidine with the E‐selectin antagonist uproleselan is an effective strategy to augment responses in myelodysplasia and acute myeloid leukaemia. Br J Haematol. 2024;204(6):2264-2274.

     [Crossref] [Google Scholar] [PubMed]

628. DeAngelo DJ, Jonas BA, Liesveld JL, Bixby DL, Advani AS, Marlton P, et al. Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022;139(8):1135-1146.

     [Crossref] [Google Scholar] [PubMed] 

629. DeAngelo DJ, Erba HP, Jonas BA, O'Dwyer M, Marlton P, Huls GA, et al. A phase Ill trial to evaluate the efficacy of uproleselan (GMI-1271) with chemotherapy in patients with relapsed/refractory acute myeloid leukemia. J Clin Oncol. 2019;37(15).

     [Crossref] [Google Scholar]

630. DeAngelo DJ, Jonas BA, Liesveld JL, Bixby DL, Advani AS, Marlton P, et al. Uproleselan (GMI-1271), an E-selectin antagonist, improves the efficacy and safety of chemotherapy in Relapsed/Refractory (R/R) and newly diagnosed older patients with acute myeloid leukemia: Final, correlative, and subgroup analyses. Blood. 2018;132:331.

     [Crossref] [Google Scholar]

631. Uy GL, DeAngelo DJ, Lozier JN, Fisher DM, Jonas BA, Magnani JL, et al. Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy. Blood Rev. 2024:101184.

     [Crossref] [Google Scholar] [PubMed]

632. Natoni A, Smith TA, Keane N, McEllistrim C, Connolly C, Jha A, et al. E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271. Leukemia. 2017;31(12):2642-2651.

     [Crossref] [Google Scholar] [PubMed]

633. Komatsuya K, Kikuchi N, Hirabayashi T, Kasahara K. The regulatory roles of cerebellar glycosphingolipid microdomains/lipid rafts. Int J Mol Sci. 2023;24(6):5566.

     [Crossref] [Google Scholar] [PubMed]

634. Jarvis WD, Grant S, Kolesnick RN. Ceramide and the induction of apoptosis. Clin Cancer Res. 1996;2(1):1-6.

     [Crossref] [Google Scholar] [PubMed]

635. Hakomori SI. Cancer-associated glycosphingolipid antigens: Their structure, organization, and function. Cells Tissues Organs. 1998;161(1-4):79-90.

     [Crossref] [Google Scholar] [PubMed] 

636. Kasahara K, Sanai Y. Possible roles of glycosphingolipids in lipid rafts. Biophys Chem. 1999;82(2-3):121-127.

     [Crossref] [Google Scholar] [PubMed] 

637. Sietsma H, Kamps WA, Dontje B, Hendriks D, Kok JW, Vellenga E, et al. Leukemia‐induced bone marrow depression: Effects of gangliosides on erythroid cell production. Int J Cancer. 1999;82(1):92-97.

     [Crossref] [Google Scholar] [PubMed]

638. Liang YJ, Kuo HH, Lin CH, Chen YY, Yang BC, Cheng YY, et al. Switching of the core structures of glycosphingolipids from globo-and lacto-to ganglio-series upon human embryonic stem cell differentiation. Proc Natl Acad Sci. 2010;107(52):22564-22569.

     [Crossref] [Google Scholar] [PubMed] 

639. Ogasawara N, Katagiri YU, Kiyokawa N, Kaneko T, Sato B, Nakajima H, et al. Accelerated biosynthesis of neolacto-series glycosphingolipids in differentiated mouse embryonal carcinoma F9 cells detected by using dodecyl N-acetylglucosaminide as a saccharide primer. J Biochem. 2011;149(3):321-330.

     [Crossref] [Google Scholar] [PubMed]

640. Zhuo D, Li X, Guan F. Biological roles of aberrantly expressed glycosphingolipids and related enzymes in human cancer development and progression. Front Physiol. 2018;9:466.

     [Crossref] [Google Scholar] [PubMed]

641. Alam S, Anugraham M, Huang YL, Kohler RS, Hettich T, Winkelbach K, et al. Altered (neo-) lacto series glycolipid biosynthesis impairs α2-6 sialylation on N-glycoproteins in ovarian cancer cells. Sci Rep. 2017;7(1):45367.

     [Crossref] [Google Scholar] [PubMed]

642. Togayachi A, Akashima T, Ookubo R, Kudo T, Nishihara S, Iwasaki H, et al. Molecular cloning and characterization of UDP-GlcNAc: Lactosylceramide β1, 3-N-acetylglucosaminyltransferase (β3Gn-T5), an essential enzyme for the expression of HNK-1 and Lewis X epitopes on glycolipids. J Biol Chem. 2001;276(25):22032-22040.

     [Crossref] [Google Scholar] [PubMed]

643. Togayachi A, Narimatsu H. UDP-GlcNAc: BetaGal Beta-1, 3-N-Acetylglucosaminyltransferase 5 (B3GNT5, Lc3Cer Synthase). Handbook of Glycosyltransferases and Related Genes.
644. Nozaki H, Yanagida M, Koide KI, Shiotani K, Kinoshita M, Kobayashi Y, et al. Production and characterization of monoclonal antibodies specific to lactotriaosylceramide. Glycobiology. 2010;20(12):1631-1642.

     [Crossref] [Google Scholar] [PubMed]

645. Zhuo D, Li X, Guan F. Biological roles of aberrantly expressed glycosphingolipids and related enzymes in human cancer development and progression. Front Physiol. 2018;9:466.

     [Crossref] [Google Scholar] [PubMed]

646. Bordessoule D, Jones M, Gatter KC, Mason DY. Immunohistological patterns of myeloid antigens: tissue distribution of CD13, CD14, CD16, CD31, CD36, CD65, CD66 and CD67. Br J Haematol. 1993;83(3):370-383.

     [Crossref] [Google Scholar] [PubMed]

647. Young Jr WW, Hakomori SI, Durdik JM, Henney CS. Identification of ganglio-N-tetraosylceramide as a new cell surface marker for murine Natural Killer (NK) cells. J Immunol. 1980;124(1):199-201.

     [Crossref] [Google Scholar] [PubMed]

648. Ossenkoppele GJ, van de Loosdrecht AA, Schuurhuis GJ. Review of the relevance of aberrant antigen expression by flow cytometry in myeloid neoplasms. Br J Haematol. 2011;153(4):421-436.

     [Crossref[ [Google Scholar] [PubMed]

649. Zhang T, de Waard AA, Wuhrer M, Spaapen RM. The role of glycosphingolipids in immune cell functions. Front Immunol. 2019;10:90.

     [Crossref] [Google Scholar] [PubMed]

650. Schnaar RL, Sandhoff R, Tiemeyer M, Kinoshita T. Glycosphingolipids. Essent Glycobiology. 2022.

     [Crossref] [Google Scholar] [PubMed]

651. Julien S, Bobowski M, Steenackers A, Le Bourhis X, Delannoy P. How do gangliosides regulate RTKs signaling. Cells. 2013;2(4):751-767.

     [Crossref] [Google Scholar] [PubMed]

652. Dorvignit D, García-Martínez L, Rossin A, Sosa K, Viera J, Hernández T, et al. Antitumor and cytotoxic properties of a humanized antibody specific for the GM3 (Neu5Gc) ganglioside. Immunobiology. 2015;220(12):1343-1350.

     [Crossref] [Google Scholar] [PubMed]

653. Ghorashi AC, Boucher A, Archer-Hartmann SA, Murray NB, Konada RS, Zhang X, et al. Fucosylated glycoproteins and fucosylated glycolipids play opposing roles in cholera intoxication. bioRxiv. 2023.

     [Crossref] [Google Scholar] [PubMed]

654. Furukawa K, Takamiya K, Furukawa K. β1, 4-N-acetylgalactosaminyltransferase-GM2/GD2 synthase: A key enzyme to control the synthesis of brain-enriched complex gangliosides. Biochim Biophys Acta. 2002;1573(3):356-362.

     [Crossref] [Google Scholar] [PubMed]

655. Nakamura M, Ogino H, Nojiri H, Kitagawa S, Saito M. Characteristic incorporation of ganglioside GM3, which induces monocytic differentiation in human myelogenous leukemia HL-60 cells. Biochem Biophys Res Commun. 1989;161(2):782-789.

     [Crossref] [Google Scholar] [PubMed]

656. Wang D, Zhang T, Madunic K, de Waard AA, Blochl C, Mayboroda OA, et al. Glycosphingolipid-glycan signatures of acute myeloid leukemia cell lines reflect hematopoietic differentiation. J Proteome Res. 2022;21(4):1029-1040.

     [Crossref] [Google Scholar] [PubMed]

657. Wang Z, Wen L, Ma X, Chen Z, Yu Y, Zhu J, et al. High expression of lactotriaosylceramide, a differentiation-associated glycosphingolipid, in the bone marrow of acute myeloid leukemia patients. Glycobiology. 2012;22(7):930-938.

     [Crossref] [Google Scholar] [PubMed]

658. Reaman GH, Taylor BJ, Merritt WD. Anti-GD3 monoclonal antibody analysis of childhood T-cell acute lymphoblastic leukemia: Detection of a target antigen for antibody-mediated cytolysis. Cancer Res. 1990;50(1):202-205.

     [Crossref] [Google Scholar] [PubMed]

659. Merritt WD, Casper JT, Lauer SJ, Reaman GH. Expression of GD3 ganglioside in childhood T-cell lymphoblastic malignancies. Cancer Res. 1987;47(6):1724-1730.

     [Crossref] [Google Scholar] [PubMed]

660. Okada M, Furukawa K, Yamashiro S, Yamada Y, Haraguchi M, Horibe K, et al. High expression of ganglioside α-2, 8-sialyltransferase (GD3 synthase) gene in adult T-cell leukemia cells unrelated to the gene expression of human T-lymphotropic virus type I. Cancer Res. 1996;56(12):2844-2848.

     [Crossref] [Google Scholar] [PubMed]

661. Yamashiro S, Ruan S, Furukawa K, Tai T, Lloyd KO, Shiku H, et al. Genetic and enzymatic basis for the differential expression of GM2 and GD2 gangliosides in human cancer cell lines. Cancer Res. 1993;53(22):5395-5400.

     [Crossref] [Google Scholar] [PubMed]

662. Furukawa K, Akagi T, Nagata Y, Yamada Y, Shimotohno K, Cheung NK, et al. GD2 ganglioside on human T-lymphotropic virus type I-infected T cells: Possible activation of beta-1, 4-N-acetylgalactosaminyltransferase gene by p40tax. Proc Natl Acad Sci U S A. 1993;90(5):1972-1976.

     [Crossref] [Google Scholar] [PubMed]

663. Fernandes DM, Baird AM, Berg LJ, Rock KL. A monoclonal antibody reactive with a 40-kDa molecule on fetal thymocytes and tumor cells blocks proliferation and stimulates aggregation and apoptosis. J Immunol. 1999;163(3):1306-1314.

     [Crossref] [Google Scholar] [PubMed]

664. Cavdarli S, Yamakawa N, Clarisse C, Aoki K, Brysbaert G, Le Doussal JM, et al. Profiling of O-acetylated gangliosides expressed in neuroectoderm derived cells. Int J Mol Sci. 2020;21(1):370.

     [Crossref] [Google Scholar] [PubMed]

665. Alvarez-Rueda N, Desselle A, Cochonneau D, Chaumette T, Clemenceau B, Leprieur S, et al. A monoclonal antibody to O-acetyl-GD2 ganglioside and not to GD2 shows potent anti-tumor activity without peripheral nervous system cross-reactivity. PLoS One. 2011;6(9):e25220.

     [Crossref] [Google Scholar] [PubMed]

666. Alvarez-Rueda N, Desselle A, Cochonneau D, Chaumette T, Clemenceau B, Leprieur S, et al. A monoclonal antibody to O-acetyl-GD2 ganglioside and not to GD2 shows potent anti-tumor activity without peripheral nervous system cross-reactivity. PLoS One. 2011;6(9):e25220.

     [Crossref] [Google Scholar] [PubMed]

667. Sorkin LS, Otto M, Baldwin III WM, Vail E, Gillies SD, Handgretinger R, et al. Anti-GD2 with an FC point mutation reduces complement fixation and decreases antibody-induced allodynia. Pain. 2010;149(1):135-142.

     [Crossref] [Google Scholar] [PubMed]

668. Fleurence J, Fougeray S, Bahri M, Cochonneau D, Clémenceau B, Paris F, et al. Targeting O‐Acetyl‐GD2 ganglioside for cancer immunotherapy. J Immunol Res. 2017;2017(1):5604891.

     [Crossref] [Google Scholar] [PubMed]

669. Kohla G, Stockfleth E, Schauer R. Gangliosides with O-acetylated sialic acids in tumors of neuroectodermal origin. Neurochem Res. 2002;27:583-592.

     [Crossref] [Google Scholar] [PubMed]

670. Kniep B, Kniep E, Özkucur N, Barz S, Bachmann M, Malisan F, et al. 9‐O‐acetyl GD3 protects tumor cells from apoptosis. Int J Cancer. 2006;119(1):67-73.

     [Crossref] [Google Scholar] [PubMed]

671. Baumann AM, Bakkers MJ, Buettner FF, Hartmann M, Grove M, Langereis MA, et al. 9-O-Acetylation of sialic acids is catalysed by CASD1 via a covalent acetyl-enzyme intermediate. Nat Commun. 2015;6(1):7673.

     [Crossref] [Google Scholar] [PubMed]

672. Mukherjee K, Chava AK, Mandal C, Dey SN, Kniep B, Chandra S, et al. O‐acetylation of GD3 prevents its apoptotic effect and promotes survival of lymphoblasts in childhood acute lymphoblastic leukaemia. J Cell Biochem. 2008;105(3):724-734.

     [Crossref] [Google Scholar] [PubMed]

673. Joo EJ, Wasik BR, Parrish C, Paz H, Mϋhlenhoff M, Abdel-Azim H, et al. Pre-B acute lymphoblastic leukemia expresses cell surface nucleolin as a 9-O-acetylated sialoglycoprotein. Sci Rep. 2018;8(1):17174.

     [Crossref] [Google Scholar] [PubMed]

674. Chen Y, Wu Z, Wang L, Lin M, Jiang P, Wen J, et al. Targeting nucleolin improves sensitivity to chemotherapy in acute lymphoblastic leukemia. Cell Oncol. 2023;46(6):1709-1724.

     [Crossref] [Google Scholar] [PubMed]

675. Ren Z, Spaargaren M, Pals ST. Syndecan-1 and stromal heparan sulfate proteoglycans: Key moderators of plasma cell biology and myeloma pathogenesis. Blood. 2021;137(13):1713-1718.

     [Crossref] [Google Scholar] [PubMed]

676. Morris AJ, Turnbull JE, Riley GP, Gordon MY, Gallagher JT. Production of heparan sulphate proteoglycans by human bone marrow stromal cells. J Cell Sci. 1991;99(1):149-156.

     [Crossref] [Google Scholar] [PubMed]

677. Le Pennec J, Picart C, Vivès RR, Migliorini E. Sweet but challenging: Tackling the complexity of GAGs with engineered tailor‐made biomaterials. Adv Mater. 2024;36(11):2312154.

     [Crossref] [Google Scholar] [PubMed]

678. Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, et al. Glycosaminoglycans: Key players in cancer cell biology and treatment. FEBS J. 2012;279(7):1177-1197.

     [Crossref] [Google Scholar] [PubMed]

679. Im A, Kim YS. Role of glycosaminoglycans in wound healing. Arch Pharm Sci Res. 2009;1(2):106-114.

     [Crossref] [Google Scholar]

680. Wu ZL, Ertelt JM. Assays for hyaluronidases and heparanase using nonreducing end fluorophore-labeled hyaluronan and heparan sulfate proteoglycan. Glycobiology. 2021;31(11):1435-1443.

     [Crossref] [Google Scholar] [PubMed]

681. Aruffo A, Stamenkovic I, Melnick M, Underhill CB, Seed B. CD44 is the principal cell surface receptor for hyaluronate. Cell. 1990;61(7):1303-1313.

     [Crossref] [Google Scholar] [PubMed]

682. Akim A, Zafar MN, Safdar N, Sung YY, Muhammad TS. Understanding hyaluronan receptor (CD44) interaction, HA-CD44 activated potential targets in cancer therapeutics. Adv Pharm Bull. 2021;11(3):426.

     [Crossref] [Google Scholar] [PubMed]

683. Chen JK, Shen CR, Liu CL. N-acetylglucosamine: Production and applications. Mar Drugs. 2010;8(9):2493-2516.

     [Crossref] [Google Scholar] [PubMed]

684. Olczyk P, Mencner L, Komosinska-Vassev K. Diverse roles of heparan sulfate and heparin in wound repair. Biomed Res Int. 2015;2015(1):549417.

     [Crossref] [Google Scholar] [PubMed]

685. Simon Davis DA, Parish CR. Heparan sulfate: A ubiquitous glycosaminoglycan with multiple roles in immunity. Front Immunol. 2013;4:470.

     [Crossref] [Google Scholar] [PubMed]

686. Nader HB, Chavante SF, Dos-Santos EA, Oliveira FW, De-Paiva JF, Jerônimo SM, et al. Heparan sulfates and heparins: Similar compounds performing the same functions in vertebrates and invertebrates. Braz J Med Biol Res. 1999;32:529-538.

     [Crossref] [Google Scholar] [PubMed]

687. Vallet SD, Annaval T, Vives RR, Richard E, Hénault J, Le Narvor C, et al. Functional and structural insights into human N‐deacetylase/N‐sulfotransferase activities. Proteoglycan Res. 2023;1(3):e8.

     [Crossref] [Google Scholar]

688. Wu Y, Bosman GP, Chapla D, Huang C, Moremen KW, de Vries RP, et al. A biomimetic synthetic strategy can provide keratan sulfate I and II oligosaccharides with diverse fucosylation and sulfation patterns. J Am Chem Soc. 2024;146(13):9230-9240.

     [Crossref] [Google Scholar] [PubMed]

689. Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK. Proteoglycans in health and disease: Novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J. 2010;277(19):3904-3923.

     [Crossref] [Google Scholar] [PubMed]

690. Li Z, Di Vagno L, Chawla H, Ni Cheallaigh A, Critcher M, Sammon D, et al. Xylosyltransferase bump-and-hole engineering to chemically manipulate proteoglycans in mammalian cells. Biorxiv. 2023.

     [Crossref] [Google Scholar]

691. Pickford CE, Holley RJ, Rushton G, Stavridis MP, Ward CM, Merry CL. Specific glycosaminoglycans modulate neural specification of mouse embryonic stem cells. Stem Cells. 2011;29(4):629-640.

     [Crossref] [Google Scholar] [PubMed]

692. Kreuger J, Jemth P, Sanders-Lindberg E, Eliahu L, Ron D, Basilico C, et al. Fibroblast growth factors share binding sites in heparan sulphate. Biochem J. 2005;389(1):145-150.

     [Crossref] [Google Scholar] [PubMed]

693. Theocharis AD, Gialeli C, Bouris P, Giannopoulou E, Skandalis SS, Aletras AJ, et al. Cell-matrix interactions: Focus on proteoglycan-proteinase interplay and pharmacological targeting in cancer. FEBS J. 2014;281(22):5023-5042.

     [Crossref] [Google Scholar] [PubMed]

694. Ricard‐Blum S, Vivès RR, Schaefer L, Götte M, Merline R, Passi A, et al. A biological guide to glycosaminoglycans: Current perspectives and pending questions. FEBS J. 2024.

     [Crossref] [Google Scholar] [PubMed]

695. Karamanos NK, Piperigkou Z, Theocharis AD, Watanabe H, Franchi M, Baud S, et al. Proteoglycan chemical diversity drives multifunctional cell regulation and therapeutics. Chem Rev. 2018;118(18):9152-9232.

     [Crossref] [Google Scholar] [PubMed]

696. Poças J, Marques C, Gomes C, Otake AH, Pinto F, Ferreira M, et al. Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival. Proc Natl Acad Sci U S A. 2023;120(20):e2214853120.

     [Crossref] [Google Scholar] [Pubmed]

697. Papy-Garcia D, Albanese P. Heparan sulfate proteoglycans as key regulators of the mesenchymal niche of hematopoietic stem cells. Glycoconj J. 2017;34:377-391.

     [Crossref] [Google Scholar] [PubMed]

698. Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol. 2011;3(7):a004952.

     [Crossref] [Google Scholar] [PubMed]

699. Matsuzaka Y, Yashiro R. Classification and molecular functions of heparan sulfate proteoglycans and their molecular mechanisms with the receptor. Biologics. 2024 Mar 28;4(2):105-29.

     [Crossref] [Google Scholar]

700. Bishop JR, Schuksz M, Esko JD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature. 2007;446(7139):1030-1037.

     [Crossref] [Google Scholar] [PubMed]

701. Wade A, Robinson AE, Engler JR, Petritsch C, James CD, Phillips JJ. Proteoglycans and their roles in brain cancer. FEBS J. 2013;280(10):2399-2417.

     [Crossref] [Google Scholar] [PubMed]

702. Vlodavsky I, Beckhove P, Lerner I, Pisano C, Meirovitz A, Ilan N, et al. Significance of heparanase in cancer and inflammation. Cancer Microenviron. 2012;5: 115-132.

     [Crossref] [Google Scholar] [PubMed]

703. Hassan N, Greve B, Espinoza-Sánchez NA, Götte M. Cell-surface heparan sulfate proteoglycans as multifunctional integrators of signaling in cancer. Cell Signal. 2021;77:109822.

     [Crossref] [Google Scholar] [PubMed]

704. Woodruff K, Setiawan N, McKay C, Root C, Meshinchi S, Termini C, et al. 3202–6-O HEPARAN SULFATION REGULATES ACUTE MYELOID LEUKEMIA CHEMOTHERAPY RESISTANCE. Experimental Hematology. 2024; 137:104522.

     [Crossref] [Google Scholar]

705. Onyeisi JO, Ferreira BZ, Nader HB, Lopes CC. Heparan sulfate proteoglycans as targets for cancer therapy: a review. Cancer Biol Ther. 2020 ;21(12):1087-1094.

     [Crossref] [Google Scholar] [Pubmed]

706. Kolset SO, Pejler G. Serglycin: A structural and functional chameleon with wide impact on immune cells. J Immunol. 2011;187(10):4927-4933.

     [Crossref] [Google Scholar] [PubMed]

707. Åbrink M, Grujic M, Pejler G. Serglycin is essential for maturation of mast cell secretory granule. J Biol Chem. 2004;279(39):40897-40905.

     [Crossref] [Google Scholar] [PubMed]

708. Theocharis AD, Seidel C, Borset M, Dobra K, Baykov V, Labropoulou V, et al. Serglycin constitutively secreted by myeloma plasma cells is a potent inhibitor of bone mineralization in vitro. J Biol Chem. 2006;281(46):35116-35128.

     [Crossref] [Google Scholar] [PubMed]

709. Skliris A, Happonen KE, Terpos E, Labropoulou V, Borset M, Heinegard D, et al. Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan chains: Implications for multiple myeloma. Eur J Immunol. 2011;41(2):437-449.

     [Crossref] [Google Scholar] [PubMed]

710. Niemann CU, Kjeldsen L, Ralfkiaer E, Jensen MK, Borregaard N. Serglycin proteoglycan in hematologic malignancies: A marker of acute myeloid leukemia. Leukemia. 2007;21(12):2406-2410.

     [Crossref] [Google Scholar] [PubMed]

711. Poças J, Marques C, Gomes C, Otake AH, Pinto F, Ferreira M, et al. Syndecan-4 is a maestro of gastric cancer cell invasion and communication that underscores poor survival. Proc Natl Acad Sci USA. 2023;120(20):2214853120.

     [Crossref] [Google Scholar] [PubMed]

712. Hagen MW, Setiawan NJ, Woodruff KA, Termini CM. Syndecans in hematopoietic cells and their niches (vol 327, pg C372, 2024). Am J of Physiol -Cell Physiol. 2024 ;327(3):C867-.

     [Crossref] [Google Scholar]

713. Dhodapkar MV, Abe E, Theus A, Lacy M, Langford JK, Barlogie B, Sanderson RD. Syndecan-1 is a multifunctional regulator of myeloma pathobiology: Control of tumor cell survival, growth, and bone cell differentiation. Blood. 1998;91(8):2679-2688.

     [Crossref] [Google Scholar] [PubMed]

714. Chilosi M, Adami F, Lestani M, Montagna L, Cimarosto L, Semenzato G, et al. CD138/syndecan-1: A useful immunohistochemical marker of normal and neoplastic plasma cells on routine trephine bone marrow biopsies. Mod Pathol. 1999;12(12):1101-1106.

     [Google Scholar] [PubMed]

715. Ridley RC, Xiao H, Hata H, Woodliff J, Epstein J, Sanderson RD. Expression of syndecan regulates human myeloma plasma cell adhesion to type I collagen. Blood. 1993;81(3):767-774.

     [Crossref] [Google Scholar] [PubMed]

716. Wijdenes J, Vooijs WC, Clément C, Post J, Morard F, Vita N, et al. A plasmocyte selective monoclonal antibody (B‐B4) recognizes syndecan‐1. Br J Haematol. 1996;94(2):318-323.

     [Crossref] [Google Scholar] [PubMed]

717. Witzig TE, Kimlinger T, Stenson M, Therneaip T. Syndecan-1 expression on malignant cells from the blood and marrow of patients with plasma cell proliferative disorders and B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 1998;31(1-2):167-175.

     [Crossref] [Google Scholar] [PubMed]

718. Dhodapkar MV, Kelly T, Theus A, Athota AB, Barlogie B, Sanderson RD. Elevated levels of shed syndecan‐1 correlate with tumour mass and decreased matrix metalloproteinase‐9 activity in the serum of patients with multiple myeloma. Br J Haematol. 1997;99(2):368-371.

     [Crossref] [Google Scholar] [PubMed]

719. Sanderson RD, Yang Y, Suva LJ, Kelly T. Heparan sulfate proteoglycans and heparanase-partners in osteolytic tumor growth and metastasis. Matrix Biol. 2004;23(6):341-352.

     [Crossref] [Google Scholar] [PubMed]

720. Seidel C, Sundan A, Hjorth M, Turesson I, Dahl IM, Abildgaard N, et al. Serum syndecan-1: A new independent prognostic marker in multiple myeloma. Blood. 2000;95(2):388-392.

     [Crossref] [Google Scholar] [PubMed]

721. Mahtouk K, Cremer FW, Reme T, Jourdan M, Baudard M, Moreaux J, et al. Heparan sulphate proteoglycans are essential for the myeloma cell growth activity of EGF-family ligands in multiple myeloma. Oncogene. 2006;25(54):7180-7191.

     [Crossref] [Google Scholar] [PubMed]

722. Yang Y, Yaccoby S, Liu W, Langford JK, Pumphrey CY, Theus A, Epstein J. Soluble syndecan-1 promotes growth of myeloma tumors in vivo. Blood. 2002;100(2):610-617.

     [Crossref] [Google Scholar] [PubMed]

723. Zhan F, Hardin J, Kordsmeier B, Bumm K, Zheng M, Tian E. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood, The Journal of the American Society of Hematology. 2002;99(5):1745-1757.

     [Crossref] [Google Scholar] [PubMed]

724. Derksen PW, Keehnen RM, Evers LM, Van Oers MH, Spaargaren M, Pals ST. Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood. 2002;99(4):1405-1410.

     [Crossref] [Google Scholar] [PubMed]

725. Spinler K, Bajaj J, Ito T, Zimdahl B, Hamilton M, Ahmadi A, et al. A stem cell reporter based platform to identify and target drug resistant stem cells in myeloid leukemia. Nat Commun. 2020;11(1):5998.

     [Crossref] [Google Scholar] [Pubmed]

726. Borsig L, Vlodavsky I, Ishai-Michaeli R, Torri G, Vismara E. Sulfated hexasaccharides attenuate metastasis by inhibition of P-selectin and heparanase. Neoplasia. 2011;13(5):445-452.

     [Crossref] [Google Scholar] [PubMed]

727. Lindahl U, Kjellén L. Pathophysiology of heparan sulphate: Many diseases, few drugs. J Intern Med. 2013;273(6):555-571.

     [Crossref] [Google Scholar] [PubMed]

728. Vlodavsky I, Ilan N, Naggi A, Casu B. Heparanase: Structure, biological functions, and inhibition by heparin-derived mimetics of heparan sulfate. Curr Pharm Des. 2007;13(20):2057-2073.

     [Crossref] [Google Scholar] [PubMed]

729. Zhang YF, Tang XD, Gao JH, Fang DC, Yang SM. Heparanase: A universal immunotherapeutic target in human cancers. Drug Discov Today. 2011;16(9-10):412-417.

     [Crossref] [Google Scholar] [PubMed]

730. Ramani VC, Purushothaman A, Stewart MD, Thompson CA, Vlodavsky I, Au JL, et al. The heparanase/syndecan‐1 axis in cancer: Mechanisms and therapies. FEBS J. 2013;280(10):2294-2306.

     [Crossref] [Google Scholar] [PubMed]

731. Sanderson RD, Elkin M, Rapraeger AC, Ilan N, Vlodavsky I. Heparanase regulation of cancer, autophagy and inflammation: New mechanisms and targets for therapy. FEBS J. 2017;284(1):42-55.

     [Crossref] [Google Scholar] [PubMed]

732. Vlodavsky I, Gross-Cohen M, Weissmann M, Ilan N, Sanderson RD. Opposing functions of heparanase-1 and heparanase-2 in cancer progression. Trends Biochem Sci. 2018;43(1):18-31.

     [Crossref] [Google Scholar] [PubMed]

733. Vlodavsky I, Singh P, Boyango I, Gutter-Kapon L, Elkin M, Sanderson RD, et al. Heparanase: From basic research to therapeutic applications in cancer and inflammation. Drug Resist Updat. 2016;29:54-75.

     [Crossref] [Google Scholar] [PubMed]

734. Boyango I, Barash U, Fux L, Naroditsky I, Ilan N, Vlodavsky I. Targeting heparanase to the mammary epithelium enhances mammary gland development and promotes tumor growth and metastasis. Matrix Biol. 2018;65:91-103.

     [Crossref] [Google Scholar] [PubMed]

735. Barash U, Cohen‐Kaplan V, Dowek I, Sanderson RD, Ilan N, Vlodavsky I. Proteoglycans in health and disease: New concepts for heparanase function in tumor progression and metastasis. FEBS J. 2010;277(19):3890-3903.

     [Crossref] [Google Scholar] [PubMed]

736. Levy-Adam F, Ilan N, Vlodavsky I. Tumorigenic and adhesive properties of heparanase. Semin Cancer Biol. 2010;20(3):153-160.

     [Crossref] [Google Scholar] [PubMed]

737. Ilan N, Elkin M, Vlodavsky I. Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int Biochem Cell Biol. 2006;38(12):2018-2039.

     [Crossref] [Google Scholar] [PubMed]

738. Parish CR, Freeman C, Hulett MD. Heparanase: A key enzyme involved in cell invasion. Biochim Biophys Acta. 2001;1471(3):99-108. 

     [Crossref] [Google Scholar] [PubMed]

739. Ferro V, Hammond E, Fairweather JK. The development of inhibitors of heparanase, a key enzyme involved in tumour metastasis, angiogenesis and inflammation. Mini Rev Med Chem. 2004;4(6):693-702.

     [Crossref] [Google Scholar] [PubMed]

740. Purushothaman A, Sanderson RD. Heparanase: A dynamic promoter of myeloma progression. Adv Exp Med Biol. 2020:331-349.

     [Crossref] [Google Scholar] [PubMed]

741. Mahtouk K, Hose D, Raynaud P, Hundemer M, Jourdan M, Jourdan E, et al. Heparanase influences expression and shedding of syndecan-1, and its expression by the bone marrow environment is a bad prognostic factor in multiple myeloma. Blood. 2007;109(11):4914-4923.

     [Crossref] [Google Scholar] [PubMed]

742. Yang Y, MacLeod V, Dai Y, Khotskaya-Sample Y, Shriver Z, Venkataraman G, et al. The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy. Blood. 2007;110(6):2041-2048.

     [Crossref] [Google Scholar] [PubMed]

743. Barash U, Zohar Y, Wildbaum G, Beider K, Nagler A, Karin N, et al. Heparanase enhances myeloma progression CXCL10 downregulation. Leukemia. 2014;28(11):2178-2187.

     [Crossref] [Google Scholar] [PubMed]

744. Li J, Pan Q, Rowan PD, Trotter TN, Peker D, Regal KM, et al. Heparanase promotes myeloma progression by inducing mesenchymal features and motility of myeloma cells. Oncotarget. 2016;7(10):11299-11309.

     [Crossref] [Google Scholar] [PubMed]

745. Tripathi K, Ramani VC, Bandari SK, Amin R, Brown EE, Ritchie JP, et al. Heparanase promotes myeloma stemness and in vivo tumorigenesis. Matrix Biol. 2020;88:53-68.

     [Crossref] [Google Scholar] [PubMed]

746. Yang Y, MacLeod V, Bendre M, Huang Y, Theus AM, Miao HQ, et al. Heparanase promotes the spontaneous metastasis of myeloma cells to bone. Blood. 2005;105(3):1303-1309.

     [Crossref] [Google Scholar] [PubMed]

747. Kelly T, Miao HQ, Yang Y, Navarro E, Kussie P, Huang Y, et al. High heparanase activity in multiple myeloma is associated with elevated microvessel density. Cancer Res. 2003;63(24):8749-8756.

     [Google Scholar] [PubMed]

748. Ramani VC, Zhan F, He J, Barbieri P, Noseda A, Tricot G, et al. Targeting heparanase overcomes chemoresistance and diminishes relapse in myeloma. Oncotarget. 2016;7(2):1598-1607.

     [Crossref] [Google Scholar] [PubMed]

749. Ramani VC, Vlodavsky I, Ng M, Zhang Y, Barbieri P, Noseda A, et al. Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype. Matrix biol. 2016;55:22-34.

     [Crossref] [Google Scholar] [PubMed]

750. Hostettler N, Naggi A, Torri G, Ishai‐Michaeli R, Casu B, Vlodavsky I, et al. P‐selectin‐and heparanase‐dependent antimetastatic activity of non‐anticoagulant heparins. FASEB J. 2007;21(13):3562-72.

     [Crossref] [Google Scholar] [PubMed]

751. Casu B, Vlodavsky I, Sanderson RD. Non-anticoagulant heparins and inhibition of cancer. Pathophysiol Haemost Thromb. 2007;36(3-4):195-203.

     [Crossref] [Google Scholar] [PubMed]

752. Masola V, Bellin G, Gambaro G, Onisto M. Heparanase: A multitasking protein involved in extracellular matrix (ECM) remodeling and intracellular events. Cells. 2018;7(12):236.

     [Crossref] [Google Scholar] [PubMed]

753. Vlodavsky I, Ilan N, Sanderson RD. Forty years of basic and translational heparanase research. Adv Exp Med Biol. 2020;1221:3-59.

     [Crossref] [Google Scholar] [PubMed]

754. Ritchie JP, Ramani VC, Ren Y, Naggi A, Torri G, Casu B, Penco S, et al. SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. Clin Cancer Res. 2011;17(6):1382-9133.

     [Crossref] [Google Scholar] [PubMed]

755. Galli M, Chatterjee M, Grasso M, Specchia G, Magen H, Einsele H, et al. Phase I study of the heparanase inhibitor roneparstat: An innovative approach for ultiple myeloma therapy. Haematologica. 2018 Oct;103(10):469-472.

     [Crossref] [Google Scholar] [PubMed]

756. Weissmann M, Arvatz G, Horowitz N, Feld S, Naroditsky I, Zhang Y, et al. Heparanase-neutralizing antibodies attenuate lymphoma tumor growth and metastasis. Proc Natl Acad Sci U S A. 2016;113(3):704-709.

     [Crossref] [Google Scholar] [PubMed]

757. Chhabra M, Wilson JC, Wu L, Davies GJ, Gandhi NS, Ferro V. Structural insights into pixatimod (PG545) inhibition of heparanase, a key enzyme in cancer and viral infections. Chemistry. 2022;28(11):202104222.

     [Crossref] [Google Scholar] [PubMed]

758. Hammond E, Haynes NM, Cullinane C, Brennan TV, Bampton D, Handley P, et al. Immunomodulatory activities of pixatimod: Emerging nonclinical and clinical data, and its potential utility in combination with PD-1 inhibitors. J Immunother Cancer. 2018;6(1):1-3.

     [Crossref] [Google Scholar] [PubMed]

759. Ferro V, Liu L, Johnstone KD, Wimmer N, Karoli T, Handley P, et al. Discovery of PG545: A highly potent and simultaneous inhibitor of angiogenesis, tumor growth, and metastasis. J Med Chem. 2012;55(8):3804-3813.

     [Crossref] [Google Scholar] [PubMed]

760. Dredge K, Brennan TV, Hammond E, Lickliter JD, Lin L, Bampton D, et al. A Phase I study of the novel immunomodulatory agent PG545 (pixatimod) in subjects with advanced solid tumours. J Med Chem. 2018;118(8):1035-41.

     [Crossref] [Google Scholar] [PubMed]

761. Hammond E, Dredge K. Heparanase Inhibition by Pixatimod (PG545): Basic aspects and future perspectives. Adv Exp Med Biol. 2020;1221:539-565.

     [Crossref] [Google Scholar] [PubMed]

762. Brennan TV, Lin L, Brandstadter JD, Rendell VR, Dredge K, Huang X, et al. Heparan sulfate mimetic PG545-mediated antilymphoma effects require TLR9-dependent NK cell activation. J Clin Invest. 2016;126(1):207-219.

     [Crossref] [Google Scholar] [PubMed]

763. Shuvalova ML, Kopylov AT, Mazurov DV, Pichugin AV, Bovin NV, Filatov AV. CD44-associated Tn antigen as a new biomarker of tumor cells with aberrant glycosylation. Biochemistry (Mosc). 2020;85(9):1064-1071.

     [Crossref] [Google Scholar] [PubMed]

764. Senbanjo LT, Chellaiah MA. CD44: A multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front Cell Dev Biol. 2017;5:18.

     [Crossref] [Google Scholar] [PubMed]

765. Biswas C. Inflammation in Systemic Immune Diseases: Role of TLR9 Signaling and the Resultant Oxidative Stress in Pathology of Lupus. InImmunity and inflammation in health and disease 2018;223-237.

     [Google Scholar]

766. Guo JY, Chiu CH, Wang MJ, Li FA, Chen JY. Proteoglycan serglycin promotes non-small cell lung cancer cell migration through the interaction of its glycosaminoglycans with CD44. J Biomed Sci. 2020;27:1-8.

     [Crossref] [Google Scholar] [PubMed]

767. Toyama-Sorimachi N, Sorimachi H, Tobita Y, Kitamura F, Yagita H, Suzuki K, et al. A novel ligand for CD44 Is serglycin, a hematopoietic cell lineage-specific proteoglycan: Possible involvement in lymphoid cell adherence and activation. J Biol Chem. 1995;270(13):7437-7444.

     [Crossref] [Google Scholar] [PubMed]

768. Guo JY, Hsu HS, Tyan SW, Li FY, Shew JY, Lee WH, et al. Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner. Oncogene. 2017;36(17):2457-2471.

     [Crossref] [Google Scholar] [PubMed]

769. Ponta H, Sherman L, Herrlich PA. CD44: From adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol. 2003;4(1):33-45.

     [Crossref] [Google Scholar] [PubMed]

770. Skelton TP, Zeng C, Nocks A, Stamenkovic I. Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan. J Cell Biol. 1998;140(2):431-446.

     [Crossref] [Google Scholar] [PubMed]

771. Liao C, Wang Q, An J, Chen J, Li X, Long Q, et al. CD44 glycosylation as a therapeutic target in oncology. Front Oncol. 2022;12:883831.

     [Crossref] [Google Scholar] [PubMed]

772. Dimitroff CJ, Lee JY, Fuhlbrigge RC, Sackstein R. A distinct glycoform of CD44 is an L-selectin ligand on human hematopoietic cells. Proc Natl Acad Sci. 2000;97(25):13841-13846.

     [Crossref] [Google Scholar] [PubMed]

773. Dimitroff CJ, Lee JY, Rafii S, Fuhlbrigge RC, Sackstein R. CD44 is a major E-selectin ligand on human hematopoietic progenitor cells. J Cell Biol. 2001;153(6):1277-1286.

     [Crossref] [Google Scholar] [PubMed]

774. Sackstein R, Dimitroff CJ. A hematopoietic cell L-selectin ligand that is distinct from PSGL-1 and displays N-glycan–dependent binding activity. Blood. 2000;96(8):2765-2774.

     [Crossref] [Google Scholar] [PubMed]

775. Xu H, Niu M, Yuan X, Wu K, Liu A. CD44 as a tumor biomarker and therapeutic target. Exp Hematol Oncol. 2020;9:1-4.

     [Crossref] [Google Scholar] [PubMed]

776. Karousou E, Misra S, Ghatak S, Dobra K, Götte M, Vigetti D, et al. Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer. Matrix Biol. 2017;59:3-22.

     [Crossref] [Google Scholar] [PubMed]

777. Toole BP, Slomiany MG. Hyaluronan, CD44 and emmprin: Partners in cancer cell chemoresistance. Drug Resist Updat. 2008;11(3):110-121.

     [Crossref] [Google Scholar] [PubMed]

778. Bourguignon LW, Zhu H, Shao L, Chen YW. CD44 interaction with c-Src kinase promotes cortactin-mediated cytoskeleton function and hyaluronic acid-dependent ovarian tumor cell migration. J Biol Chem. 2001 9;276(10):7327-7336.

     [Crossref] [Google Scholar] [PubMed]

779. Zöller M. CD44: Can a cancer-initiating cell profit from an abundantly expressed molecule. Nat Rev Cancer. 2011;11(4):254-267.

     [Crossref] [Google Scholar] [PubMed]

780. Liu J, Jiang G. CD44 and hematologic malignancies. Cell Mol Immunol. 2006;3(5):359-365.

     [Crossref] [Google Scholar] [PubMed]

781. Zoeller M. CD44, hyaluronan, the hematopoietic stem cell, and leukemia-initiating cells. Front Immunol. 2015;6:235.

     [Crossref] [Google Scholar] [PubMed]

782. Barkeer S, Chugh S, Batra SK, Ponnusamy MP. Glycosylation of cancer stem cells: Function in stemness, tumorigenesis, and metastasis. Neoplasia. 2018;20(8):813-825.

     [Crossref] [Google Scholar] [PubMed]

783. Yan Y, Zuo X, Wei D. Concise review: Emerging role of CD44 in cancer stem cells: A promising biomarker and therapeutic target. Stem Cells Transl Med. 2015;4(9):1033-1043.

     [Crossref] [Google Scholar] [PubMed]

784. Hassn Mesrati M, Syafruddin SE, Mohtar MA, Syahir A. CD44: A multifunctional mediator of cancer progression. Biomolecules. 2021;11(12):1850.

     [Crossref] [Google Scholar] [PubMed]

785. Piya S, Yang Y, Bhattacharya S, Sharma P, Ma H, Mu H, et al. Targeting the NOTCH1-MYC-CD44 axis in leukemia-initiating cells in T-ALL. Leukemia. 2022;36(5):1261-1273.

     [Crossref] [Google Scholar] [PubMed]

786. Lapidot T, Dar A, Kollet O. How do stem cells find their way home. Blood. 2005;106(6):1901-1910.

     [Crossref] [Google Scholar] [PubMed]

787. Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE. Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med. 2006;12(10):1167-1174.

     [Crossref] [Google Scholar] [PubMed]

788. Charrad RS, Li Y, Delpech B, Balitrand N, Clay D, Jasmin C, et al. Ligation of the CD44 adhesion molecule reverses blockage of differentiation in human acute myeloid leukemia. Nat Med. 1999;5(6):669-676.

     [Crossref] [Google Scholar] [PubMed]

789. Vaskova M, Mejstrikova E, Kalina T, Martinkova P, Omelka M, Trka J, et al. Transfer of genomics information to flow cytometry: Expression of CD27 and CD44 discriminates subtypes of acute lymphoblastic leukemia. Leukemia. 2005;19(5):876-878.

     [Crossref] [Google Scholar] [PubMed]

790. Chang G, Zhang H, Wang J, Zhang Y, Xu H, Wang C, et al. CD44 targets Wnt/β-catenin pathway to mediate the proliferation of K562 cells. Cancer Cell Int. 2013;13:1-3.

     [Crossref] [Google Scholar] [PubMed]

791. Bei Y, He J, Dong X, Wang Y, Wang S, Guo W, et al. Targeting CD44 variant 5 with an antibody–drug conjugate is an effective therapeutic strategy for intrahepatic cholangiocarcinoma. Cancer Res. 2023;83(14):2405-2420.

     [Crossref] [Google Scholar] [PubMed]

792. Rall CJ, Rustgi AK. CD44 isoform expression in primary and metastatic pancreatic adenocarcinoma. Cancer Res. 1995;55(9):1831-1835.

     [Crossref] [Google Scholar] [PubMed]

793. Naor D, Sionov RV, Ish-Shalom D. CD44: Structure, function and association with the malignant process. Adv Cancer Res. 1997;71:241-319.

     [Crossref] [Google Scholar] [PubMed]

794. Mackay CR, Terpe HJ, Stauder R, Marston WL, Stark H, Günthert U. Expression and modulation of CD44 variant isoforms in humans. J Cell Biol. 1994;124(1):71-82.

     [Crossref] [Google Scholar] [PubMed]

795. Matsumura Y, Tarin D. Significance of CD44 gene products for cancer diagnosis and disease evaluation. Lancet. 1992;340(8827):1053-1058.

     [Crossref] [Google Scholar] [PubMed]

796. Eisterer W, Bechter O, Söderberg O, Nilsson K, Terol M, Greil R, et al. Elevated levels of soluble CD44 are associated with advanced disease and in vitro proliferation of neoplastic lymphocytes in B-cell chronic lymphocytic leukaemia. Leuk Res. 2004;28(10):1043-1051.

     [Crossref] [Google Scholar] [PubMed]

797. Molica S, Vitelli G, Levato D, Giannarelli D, Gandolfo GM. Elevated serum levels of soluble CD44 can identify a subgroup of patients with early B‐cell chronic lymphocytic leukemia who are at high risk of disease progression. Cancer. 2001;92(4):713-719.

     [Crossref] [Google Scholar] [PubMed]

798. Ristamäki R, Joensuu H, Salmi M, Jalkanen S. Serum CD44 in malignant lymphoma: An association with treatment response. Blood. 1994;84(1):238-243.

     [Crossref] [Google Scholar] [PubMed]

799. Ristamäki R, Joensuu H, Lappalainen K, Teerenhovi L, Jalkanen S. Elevated serum CD44 level is associated with unfavorable outcome in non-Hodgkin's lymphoma. Blood. 1997;90(10):4039-4045.

     [Crossref] [Google Scholar] [PubMed]

800. Taçyildiz N, Çavdar AO, Yavuz G, Gözdaşoglu S, Ünal E, Ertem U, et al. Serum levels and differential expression of CD44 in childhood leukemia and malignant lymphoma: Correlation with prognostic criteria and survival. Pediatr Int. 2001;43(4):354-360.

     [Crossref] [Google Scholar] [PubMed]

801. Erb U, Megaptche AP, Gu X, Büchler MW, Zöller M. CD44 standard and CD44v10 isoform expression on leukemia cells distinctly influences niche embedding of hematopoietic stem cells. J Hematol Oncol. 2014;7:1-9.

     [Crossref] [Google Scholar] [PubMed]

802. Chen C, Zhao S, Karnad A, Freeman JW. The biology and role of CD44 in cancer progression: Therapeutic implications. J Hematol Oncol. 2018;11:1-23.

     [Crossref] [Google Scholar] [PubMed]

803. Misra S, Heldin P, Hascall VC, Karamanos NK, Skandalis SS, Markwald RR, et al. Hyaluronan–CD44 interactions as potential targets for cancer therapy. FEBS J. 2011;278(9):1429-1443.

     [Crossref] [Google Scholar] [PubMed]

804. Orian-Rousseau V, Sleeman J. CD44 is a multidomain signaling platform that integrates extracellular matrix cues with growth factor and cytokine signals. Adv Cancer Res. 2014;123:231-254.

     [Crossref] [Google Scholar] [PubMed]

805. Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours. Eur J Cancer. 2010;46(7):1271-1277.

     [Crossref] [Google Scholar] [PubMed]

806. Thapa R, Wilson GD. The importance of CD44 as a stem cell biomarker and therapeutic target in cancer. Stem Cells Int. 2016;2016(1):2087204.

     [Crossref] [Google Scholar] [PubMed]

807. Zarcone D, De Rossi G, Tenca C, Marroni P, Mauro FR, Cerruti GM, et al. Functional and clinical relevance of CD44 variant isoform expression on B-cell chronic lymphocytic leukemia cells. Haematologica. 1998;83(12):1088-1098.

     [Google Scholar] [PubMed]

808. Zhang S, Wu CC, Fecteau JF, Cui B, Chen L, Zhang L, et al. Targeting chronic lymphocytic leukemia cells with a humanized monoclonal antibody specific for CD44. Proc Natl Acad Sci U S A. 2013;110(15):6127-6132.

     [Crossref] [Google Scholar] [PubMed]

809. Loh TJ, Moon H, Cho S, Jung DW, Hong SE, Kim DH, et al. SC35 promotes splicing of the C5-V6-C6 isoform of CD44 pre-mRNA. Oncol Rep. 2014;31(1):273-279.

     [Crossref] [Google Scholar] [PubMed]

810. Spiegelberg D, Nilvebrant J. CD44v6-targeted imaging of head and neck squamous cell carcinoma: Antibody-based approaches. Contrast Media Mol Imaging. 2017;2017(1):2709547.

     [Crossref] [Google Scholar] [PubMed]

811. Günthert U, Hofmann M, Rudy W, Reber S, Zöller M, Hauβmann I, et al. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell.1991;65(1):13-24.

     [Crossref] [Google Scholar] [PubMed]

812. Wang Z, Zhao K, Hackert T, Zöller M. CD44/CD44v6 a reliable companion in cancer-initiating cell maintenance and tumor progression. Front Cell Dev Biol. 2018;6:97.

     [Crossref] [Google Scholar] [PubMed]

813. Legras S, Gunthert U, Stauder R, Curt F, Oliferenko S, Kluin Nelemans HC, et al. A strong expression of CD44-6v correlates with shorter survival of patients with acute myeloid leukemia. Blood. 1998;91(9):3401-3413.

     [Crossref] [Google Scholar] [PubMed]

814. Liebisch P, Eppinger S, Schopflin C, Stehle G, Munzert G, Dohner H, et al. CD44v6, a target for novel antibody treatment approaches, is frequently expressed in multiple myeloma and associated with deletion of chromosome arm 13q. Haematologica. 2005;90(4):489-493.

     [Google Scholar] [PubMed]

815. Casucci M, Nicolis di Robilant B, Falcone L, Camisa B, Norelli M, Genovese P, et al. CD44v6-targeted T cells mediate potent antitumor effects against acute myeloid leukemia and multiple myeloma. Blood. 2013;122(20):3461-3472.

     [Crossref] [Google Scholar] [PubMed]

816. Ding L, Hu Y, Huang H. Novel progresses of chimeric antigen receptor (CAR) T cell therapy in multiple myeloma. Stem Cell Investig. 2021;8.

     [Crossref] [Google Scholar] [PubMed]

817. Asosingh K, Günthert U, Bakkus MH, De Raeve H, Goes E, Van Riet I, et al. In vivo induction of insulin-like growth factor-I receptor and CD44v6 confers homing and adhesion to murine multiple myeloma cells. Cancer Res. 2000;60(11):3096-3104.

     [Google Scholar] [PubMed]

818. Stauder R, Eisterer W, Thaler J, Gunthert U. CD44 variant isoforms in non-Hodgkin's lymphoma: a new independent prognostic factor. Blood. 1995;85(10):2885-2899.

     [Google Scholar] [PubMed]

819. Hertweck MK, Erdfelder F, Kreuzer KA. CD44 in hematological neoplasias. Ann Hematol. 2011;90:493-508.

     [Crossref] [Google Scholar] [PubMed]

820. Ristamäki R, Joensuu H, Söderström KO, Jalkanen S. CD44v6 expression in non‐Hodgkin's lymphoma: An association with low histological grade and poor prognosis. J Pathol.1995;176(3):259-267.

     [Crossref] [Google Scholar] [PubMed]

821. Inagaki H, Banno S, Wakita A, Ueda R, Eimoto T. Prognostic significance of CD44v6 in diffuse large B-cell lymphoma. Mod Pathol. 1999;12(5):546-552.

     [Google Scholar] [PubMed]

822. Zarcone D, De Rossi G, Tenca C, Marroni P, Mauro FR, Cerruti GM, et al. Functional and clinical relevance of CD44 variant isoform expression on B-cell chronic lymphocytic leukemia cells. Haematologica. 1998;83(12):1088-1098.

     [Google Scholar] [PubMed]

823. Magyarosy E, Sebestyen A, Timar J. Expression of metastasis associated proteins, CD44v6 and NM23-H1, in pediatric acute lymphoblastic leukemia. Anticancer Res. 2001;21(1B):819-823.

     [Google Scholar] [PubMed]

824. Bendall LJ, Nilsson SK, Khan NI, James A, Bonnet C, Lock RB, et al. Role of CD44 variant exon 6 in acute lymphoblastic leukaemia: Association with altered bone marrow localisation and increased tumour burden. Leukemia. 2004;18(7):1308-11.

     [Crossref] [Google Scholar] [PubMed]

825. Singh R, Campbell BJ, Yu LG, Fernig DG, Milton JD, Goodlad RA, et al. Cell surface–expressed thomsen-friedenreich antigen in colon cancer is predominantly carried on high molecular weight splice variants of CD44. Glycobiology. 2001;11(7):587-592.

     [Crossref] [Google Scholar] [PubMed]

826. Campos D, Freitas D, Gomes J, Magalhaes A, Steentoft C, Gomes C, et al. Probing the O-glycoproteome of gastric cancer cell lines for biomarker discovery*[S]. Mol Cell Proteomics. 2015;14(6):1616-1629.

     [Crossref] [Google Scholar] [PubMed]

827. Barkeer S, Chugh S, Karmakar S, Kaushik G, Rauth S, Rachagani S, et al. Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells. BMC Cancer. 2018; 18:1-5.

     [Crossref] [Google Scholar] [PubMed]

828. Stauder R, Van Driel M, Schwarzler C, Thaler J, Lokhorst HM, Kreuser ED, et al. Different CD44 splicing patterns define prognostic subgroups in multiple myeloma.Blood.1996;88(8):3101-3108

     [Google Scholar] [PubMed]

829. Eisterer W, Bechter O, Hilbe W, Van Driel M, Lokhorst HM, Thaler J, et al. CD44 isoforms are differentially regulated in plasma cell dyscrasias and CD44v9 represents a new independent prognostic parameter in multiple myeloma. Leuk Res. 2001;25(12):1051-1057.

     [Crossref] [Google Scholar] [PubMed]

830. Beham Schmid C, Heider KH, Hoefler G, Zatloukal K. Expression of CD44 splice variant v10 in hodgkin's disease is associated with aggressive behaviour and high risk of relapse. J Pathol. 1998;186(4):383-389.

     [Crossref] [Google Scholar] [PubMed]

831. Holm F, Hellqvist E, Mason CN, Ali SA, Delos Santos N, Barrett CL, et al. Reversion to an embryonic alternative splicing program enhances leukemia stem cell self-renewal. Proc Natl Acad Sci U S A. 2015;112(50):15444-15449.

     [Crossref] [Google Scholar] [PubMed]

832. Holborough Kerkvliet MD, Mucignato G, Moons SJ, Psomiadou V, Konada RS, Pedowitz NJ, et al. A photoaffinity glycan-labeling approach to investigate immunoglobulin glycan-binding partners. Glycobiology. 2023;33(9):732-744.

     [Crossref] [Google Scholar] [PubMed]

833. Efremov DG, Turkalj S, Laurenti L. Mechanisms of B cell receptor activation and responses to B cell receptor inhibitors in B cell malignancies. Cancers. 2020;12(6):1396.

     [Crossref] [Google Scholar] [PubMed]

834. Young RM, Phelan JD, Wilson WH, Staudt LM. Pathogenic B‐cell receptor signaling in lymphoid malignancies: new insights to improve treatment. Immunol Rev. 2019;291(1):190-213.

     [Crossref] [Google Scholar] [PubMed]

835. Thurner L, Hartmann S, Neumann F, Hoth M, Stilgenbauer S, Küppers R, et al. Role of specific B-cell receptor antigens in lymphomagenesis. Front Oncol. 2020; 10:604685.

     [Crossref] [Google Scholar] [PubMed]

836. Burger JA, Chiorazzi N. B cell receptor signaling in chronic lymphocytic leukemia. Trends Immunol. 2013;34(12):592-601.

     [Crossref] [Google Scholar] [PubMed]

837. Kraus M, Alimzhanov MB, Rajewsky N, Rajewsky K. Survival of resting mature B lymphocytes depends on BCR signaling via the Igα/β heterodimer. Cell. 2004;117(6):787-800.

     [Crossref] [Google Scholar] [PubMed]

838. Pierce SK. Lipid rafts and B-cell activation. Nat Rev Immunol. 2002;2(2):96-105.

     [Crossref] [Google Scholar] [PubMed]

839. Lam KP, Kühn R, Rajewsky K. In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death.Cell.1997;90(6):1073-1083.

     [Crossref] [Google Scholar] [PubMed]

840. Wemlinger SM, Parker Harp CR, Yu B, Hardy IR, Seefeldt M, Matsuda J, et al. Preclinical analysis of candidate anti-human CD79 therapeutic antibodies using a humanized CD79 mouse model. J Immunol. 2022;208(7):1566-1584.

     [Crossref] [Google Scholar] [PubMed]

841. Fong CC, Spencer J, Howlett Prieto Q, Feng X, Reder AT. Adaptive and innate immune responses in multiple sclerosis with anti-CD20 therapy: Gene expression and protein profiles. Front Neurol. 2023;14: 1158487.

     [Crossref] [Google Scholar] [PubMed]

842. Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5(4):251-262.

     [Crossref] [Google Scholar] [PubMed]

843. Meeker T, Lowder J, Cleary ML, Stewart S, Warnke R, Sklar J, et al. Emergence of idiotype variants during treatment of B-cell lymphoma with anti-idiotype antibodies. N Engl J Med. 1985;312(26):1658-1665.

     [Crossref] [Google Scholar] [PubMed]

844. Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, et al. Genetic and functional drivers of diffuse large B cell lymphoma. Cell. 2017;171(2):481-494.

     [Crossref] [Google Scholar] [PubMed]

845. Phelan JD, Young RM, Webster DE, Roulland S, Wright GW, Kasbekar M, et al. A multiprotein supercomplex controlling oncogenic signalling in lymphoma. Nature. 2018;560(7718):387-91.

     [Crossref] [Google Scholar] [PubMed]

846. Wright GW, Phelan JD, Coulibaly ZA, Roulland S, Young RM, Wang JQ, et al. A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications. Cancer cell. 2020;37(4):551-568.

     [Crossref] [Google Scholar] [PubMed]

847. Huse K, Bai B, Hilden VI, Bollum LK, Våtsveen TK, Munthe LA, et al. Mechanism of CD79A and CD79B support for IgM+ B cell fitness through B cell receptor surface expression. J Immunol. 2022;209(10):2042-2053.

     [Crossref] [Google Scholar] [PubMed]

848. Myklebust JH, Brody J, Kohrt HE, Kolstad A, Czerwinski DK, Wälchli S, et al. Distinct patterns of B-cell receptor signaling in non-hodgkin lymphomas identified by single-cell profiling. Blood. 2017;129(6):759-770.

     [Crossref] [Google Scholar] [PubMed] 

849. Giovannone N, Smith LK, Treanor B, Dimitroff CJ. Galectin-glycan interactions as regulators of B cell immunity. Front Immunol. 2018; 9:2839.

     [Crossref] [Google Scholar] [PubMed]

850. Krysov S, Potter KN, Mockridge CI, Coelho V, Wheatley I, Packham G, et al. Surface IgM of CLL cells displays unusual glycans indicative of engagement of antigen in vivo. Blood. 2010;115(21):4198-4205.

     [Crossref] [Google Scholar] [PubMed]

851. Ternynck T, Dighiero G, Follezou J, Binet JL. Comparison of normal and CLL lymphocyte surface Ig determinants using peroxidase-labeled antibodies. I. Detection and quantitation of light chain determinants. Blood. 1974;43(6):789-795.  

     [Crossref] [Google Scholar] [PubMed]

852. Dighiero G, Bodega E, Mayzner R, Binet JL. Individual cell-by-cell quantitation of lymphocyte surface membrane Ig in normal and CLL lymphocyte and during ontogeny of mouse B lymphocytes by immunoperoxidase assay. Blood.1980;55(1):93-100

     [Google Scholar] [PubMed]

853. Matutes E, Owusu Ankomah K, Morilla R, Houlihan A, Que TH, Catovsky D. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia. 1994;8(10):1640-1645.  

     [Google Scholar] [PubMed]

854. Vuillier F, Dumas G, Magnac C, Prevost MC, Lalanne AI, Oppezzo P, et al. Lower levels of surface B-cell-receptor expression in chronic lymphocytic leukemia are associated with glycosylation and folding defects of the μ and CD79a chains. Blood. 2005;105(7):2933-2940.

     [Crossref] [Google Scholar] [PubMed]

855. Coelho V, Krysov S, Ghaemmaghami AM, Emara M, Potter KN, Johnson P, et al. Glycosylation of surface Ig creates a functional bridge between human follicular lymphoma and microenvironmental lectins. Proc Natl Acad Sci USA. 2010;107(43):18587-18592.

     [Crossref] [Google Scholar] [PubMed]

856. Zhu D, McCarthy H, Ottensmeier CH, Johnson P, Hamblin TJ, Stevenson FK. Acquisition of potential N-glycosylation sites in the immunoglobulin variable region by somatic mutation is a distinctive feature of follicular lymphoma. Blood. 2002;99(7):2562-2568.

     [Crossref] [Google Scholar] [PubMed]

857. Küppers R, Stevenson FK. Critical influences on the pathogenesis of follicular lymphoma. Blood. 2018;131(21):2297-2306.

     [Crossref] [Google Scholar] [PubMed]

858. Radcliffe CM, Arnold JN, Suter DM, Wormald MR, Harvey DJ, Royle L, et al. Human follicular lymphoma cells contain oligomannose glycans in the antigen-binding site of the B-cell receptor. J Biol Chem. 2007;282(10):7405-7415.

     [Crossref] [Google Scholar] [PubMed]

859. McCann KJ, Ottensmeier CH, Callard A, Radcliffe CM, Harvey DJ, Dwek RA, et al. Remarkable selective glycosylation of the immunoglobulin variable region in follicular lymphoma. Mol Immunol. 2008;45(6):1567-1572.

     [Crossref] [Google Scholar] [PubMed]

860. Valle-Argos B, Chiodin G, Bryant DJ, Taylor J, Lemm E, Duriez PJ, et al. DC-SIGN binding to mannosylated B-cell receptors in follicular lymphoma down-modulates receptor signaling capacity. Sci Rep. 2021;11(1):11676.

     [Crossref] [Google Scholar] [PubMed]

861. Linley A, Krysov S, Ponzoni M, Johnson PW, Packham G, Stevenson FK. Lectin binding to surface Ig variable regions provides a universal persistent activating signal for follicular lymphoma cells. Blood. 2015;126(16):1902-1910.

     [Crossref] [Google Scholar] [PubMed]

862. Strout MP. Sugar-coated signaling in follicular lymphoma. Blood. 2015;126(16):1871-1872.

     [Crossref] [Google Scholar] [PubMed]

863. Chiodin G, Allen JD, Bryant DJ, Rock P, Martino EA, Valle Argos B, et al. Insertion of atypical glycans into the tumor antigen-binding site identifies DLBCLs with distinct origin and behavior. Blood. 2021;138(17):1570-1582.

     [Crossref] [Google Scholar] [PubMed]

864. Janeway C, Travers P, Walport M, Shlomchik M. Immunobiology: The immune system in health and disease. New York: Garland Pub; 2001.

     [Google Scholar]

865. James LK. B cells defined by immunoglobulin isotypes. Clin Exp Immunol. 2022 ;210(3):230-239.

     [Crossref] [Google Scholar] [PubMed]

866. Schroeder Jr HW, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010;125(2): S41-S52.

     [Crossref] [Google Scholar] [PubMed]

867. van de Bovenkamp FS, Hafkenscheid L, Rispens T, Rombouts Y. The emerging importance of IgG Fab glycosylation in immunity. J Immunol. 2016;196(4):1435-1441.

     [Crossref] [Google Scholar] [PubMed]

868. Reily C, Stewart TJ, Renfrow MB, Novak J. Glycosylation in health and disease. Nat Rev Nephrol. 2019;15(6):346-366.

     [Crossref] [Google Scholar] [PubMed]

869. Trzos S, Link Lenczowski P, Pocheć E. The role of N-glycosylation in B-cell biology and IgG activity. The aspects of autoimmunity and anti-inflammatory therapy. Front Immunol. 2023; 14:1188838.

     [Crossref] [Google Scholar] [PubMed]

870. Kissel T, Derksen VF, Bentlage AE, Koeleman C, Hafkenscheid L, van der Woude D, et al. N-linked Fc glycosylation is not required for IgG-B-cell receptor function in a GC-derived B-cell line. Nat Commun 2024;15(1):393.

     [Crossref] [Google Scholar] [PubMed]

871. McCord KA, Wang C, Anhalt M, Poon WW, Gavin AL, Wu P, et al. Dissecting the ability of siglecs to antagonize fcγ receptors. ACS Cent Sci. 2024;10(2):315-330.

     [Crossref] [Google Scholar] [PubMed]

872. Hmiel LK, Brorson KA, Boyne MT. Post-translational structural modifications of immunoglobulin G and their effect on biological activity. Anal Bioanal Chem. 2015; 407:79-94.

     [Crossref] [Google Scholar] [PubMed]

873. van De Bovenkamp FS, Derksen NI, Ooijevaar de Heer P, Van Schie KA, Kruithof S, Berkowska MA, et al. Adaptive antibody diversification through N-linked glycosylation of the immunoglobulin variable region. Proc Natl Acad Sci USA. 2018;115(8):1901-1906.

     [Crossref] [Google Scholar] [PubMed]

874. Langerhorst P, Baerenfaenger M, Kulkarni P, Nadal S, Wijnands C, Post MA, et al. N-linked glycosylation of the M-protein variable region: Glycoproteogenomics reveals a new layer of personalized complexity in multiple myeloma. Clin Chem Lab Med.2024 (0).

     [Crossref] [Google Scholar] [PubMed]

875. Ortiz de Landazuri I, Oliver Caldés A, Español Rego M, Agulló C, Contreras MT, Zabaleta A, et al. Serum mass spectrometry for treatment monitoring in patients with multiple myeloma receiving ARI0002h CAR T‐cells. Br J Haematol. 2024;205(4):1346-1355.

     [Crossref] [Google Scholar] [PubMed]

876. Dispenzieri A, Larson DR, Rajkumar SV, Kyle RA, Kumar SK, Kourelis T, et al. N-glycosylation of monoclonal light chains on routine MASS-FIX testing is a risk factor for MGUS progression. Leukemia. 2020;34(10):2749-2753.

     [Crossref] [Google Scholar] [PubMed]

877. Omtvedt LA, Bailey D, Renouf DV, Davies MJ, Paramonov NA, Haavik S, et al. Glycosylation of immunoglobulin light chains associated with amyloidosis. Amyloid. 2000;7(4):227-244.

     [Crossref] [Google Scholar] [PubMed]

878. Haslund Gourley BS, Wigdahl B, Comunale MA. IgG N-glycan signatures as potential diagnostic and prognostic biomarkers. Diagnostics. 2023;13(6):1016.

     [Crossref] [Google Scholar] [PubMed]

879. Mittermayr S, Lê GN, Clarke C, Millán Martín S, Larkin AM, O’Gorman P, et al. Polyclonal Immunoglobulin GN-Glycosylation in the pathogenesis of plasma cell disorders. J Proteome Res. 2017;16(2):748-762.

     [Crossref] [Google Scholar] [PubMed]

880. Mattox DE, Bailey Kellogg C. Comprehensive analysis of lectin-glycan interactions reveals determinants of lectin specificity. PLoS Comput Biol. 2021;17(10): e1009470.

     [Crossref] [Google Scholar] [PubMed]

881. Weis WI, Taylor ME, Drickamer K. The C‐type lectin superfamily in the immune system. Immunol Rev. 1998;163(1):19-34.

     [Crossref] [Google Scholar] [PubMed]

882. van Kooyk Y, Rabinovich GA. Protein-glycan interactions in the control of innate and adaptive immune responses. Nat Immunol. 2008 ;9(6):593-601.

     [Crossref] [Google Scholar] [PubMed]

883. Clark MC, Baum LG. T cells modulate glycans on CD43 and CD45 during development and activation, signal regulation, and survival. Ann N Y Acad Sci. 2012;1253(1):58-67.

     [Crossref] [Google Scholar] [PubMed]

884. MA V. Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures. Blood. 2006;108: 2095-2105.

     [Crossref] [Google Scholar] [PubMed]

885. Al Barashdi MA, Ali A, McMullin MF, Mills K. Protein tyrosine phosphatase receptor type C (PTPRC or CD45). J Clin Pathol. 2021;74(9):548-552.

     [Crossref] [Google Scholar] [PubMed]

886. Tachibana K, Yamane J, Haghparast SM, Miyake J. Sialomucin and phosphorylated-ERM are inhibitors for cadherin-mediated aggregate formation. Biochem Biophys Res Commun. 2019;520(1):159-165.

     [Crossref] [Google Scholar] [PubMed]

887. Pillai S, Netravali IA, Cariappa A, Mattoo H. Siglecs and immune regulation. Annu Rev Immunol. 2012;30(1):357-392.

     [Crossref] [Google Scholar] [PubMed]

888. Cedeno Laurent F, Dimitroff CJ. Galectins and their ligands: Negative regulators of anti-tumor immunity. Glycoconj J. 2012; 29:619-625. 

     [Crossref] [Google Scholar] [PubMed]

889. Drickamer K, Taylor ME. Recent insights into structures and functions of C-type lectins in the immune system. Curr Opin Struct Biol. 2015; 34:26-34.

     [Crossref] [Google Scholar] [PubMed]

890. Mayer S, Raulf MK, Lepenies B. C-type lectins: Their network and roles in pathogen recognition and immunity. Histochem Cell Biol. 2017; 147:223-237.

     [Crossref] [Google Scholar] [PubMed]

891. Kremsreiter SM, Kroell AS, Weinberger K, Boehm H. Glycan-lectin interactions in cancer and viral infections and how to disrupt them. Int J Mol Sci. 2021;22(19):10577.

     [Crossref] [Google Scholar] [PubMed]

892. Monzavi Karbassi B, Pashov A, Kieber Emmons T. Tumor-associated glycans and immune surveillance. Vaccines. 2013;1(2):174-203.

     [Crossref] [Google Scholar] [PubMed]

893. Barthel SR, Hays DL, Yazawa EM, Opperman M, Walley KC, Nimrichter L, et al. Definition of molecular determinants of prostate cancer cell bone extravasation. Cancer Res. 2013;73(2):942-952.

     [Crossref] [Google Scholar] [PubMed]

894. Drickamer K, Taylor ME. Identification of lectins from genomic sequence data. Methods Enzymol.2003;362:560-567).

     [Crossref] [Google Scholar] [PubMed]

895. Islam MK, Khan M, Gidwani K, Witwer KW, Lamminmäki U, Leivo J. Lectins as potential tools for cancer biomarker discovery from extracellular vesicles. Biomark Res. 2023;11(1):85.

     [Crossref] [Google Scholar] [PubMed]

896. Van Vliet SJ, García Vallejo JJ, Van Kooyk Y. Dendritic cells and C‐type lectin receptors: Coupling innate to adaptive immune responses. Immunol Cell Biol. 2008;86(7):580-587.

     [Crossref] [Google Scholar] [PubMed

897. Anderluh M, Berti F, Bzducha Wróbel A, Chiodo F, Colombo C, Compostella F, et al. Recent advances on smart glycoconjugate vaccines in infections and cancer. FEBS J.2022;289(14):4251-4303.

     [Crossref] [Google Scholar] [PubMed]

898. Pulendran B, Palucka K, Banchereau J. Sensing pathogens and tuning immune responses. Science. 2001;293(5528):253-256. 

     [Crossref] [Google Scholar] [PubMed]

899. James LK. B cells defined by immunoglobulin isotypes. Clin Exp Immunol. 2022;210(3):230-239.

     [Crossref] [Google Scholar] [PubMed]

900. Hogarth PM. Fc receptors: Introduction. Immunol Rev. 2015;268(1):1-5.

     [Crossref] [Google Scholar] [PubMed]

901. García Vallejo JJ, Van Kooyk Y. Endogenous ligands for C‐type lectin receptors: The true regulators of immune homeostasis. Immunol Rev. 2009;230(1):22-37.

     [Crossref] [Google Scholar] [PubMed]

902. Castenmiller C, Keumatio Doungtsop BC, van Ree R, de Jong EC, van Kooyk Y. Tolerogenic immunotherapy: Targeting DC surface receptors to induce antigen-specific tolerance. Front Immunol. 2021; 12:643240.

     [Crossref] [Google Scholar] [PubMed]

903. Ding D, Yao Y, Zhang S, Su C, Zhang Y. C‑type lectins facilitate tumor metastasis. Oncol Lett. 2017;13(1):13-21.

     [Crossref] [Google Scholar] [PubMed]

904. Monteiro JT, Lepenies B. Myeloid C-type lectin receptors in viral recognition and antiviral immunity. Viruses. 2017;9(3):59.

     [Crossref] [Google Scholar] [PubMed]

905. Del Fresno C, Iborra S, Saz Leal P, Martínez López M, Sancho D. Flexible signaling of myeloid C-type lectin receptors in immunity and inflammation. Front Immunol. 2018; 9:804.

     [Crossref] [Google Scholar] [PubMed]

906. Iborra S, Sancho D. Signalling versatility following self and non-self sensing by myeloid C-type lectin receptors. Immunobiology. 2015;220(2):175-184.

     [Crossref] [Google Scholar] [PubMed]

907. Brown GD, Willment JA, Whitehead L. C-type lectins in immunity and homeostasis. Nat.Rev.Immunol. 2018;18(6):374-389.

     [Crossref] [Google Scholar] [PubMed]

908. da Costa V, Freire T. Advances in the immunomodulatory properties of glycoantigens in cancer. Cancers. 2022;14(8):1854.

     [Crossref] [Google Scholar] [PubMed]

909. Gijzen K, Raymakers RA, Broers KM, Figdor CG, Torensma R. Interaction of acute lymphopblastic leukemia cells with C-type lectins DC-SIGN and L-SIGN. Exp Hematol. 2008;36(7):860-870.

     [Crossref] [Google Scholar] [PubMed]

910. Reis CA, Osorio H, Silva L, Gomes C, David L. Alterations in glycosylation as biomarkers for cancer detection. J Clin Pathol. 2010;63(4):322-329.

     [Crossref] [Google Scholar] [PubMed]

911. van Vliet SJ, Saeland E, van Kooyk Y. Sweet preferences of MGL: Carbohydrate specificity and function. Trends Immunol. 2008;29(2):83-90.

     [Crossref] [Google Scholar] [PubMed]

912. Suzuki N, Yamamoto K, Toyoshima S, Osawa T, Irimura T. Molecular cloning and expression of cDNA encoding human macrophage C-type lectin. Its unique carbohydrate binding specificity for Tn antigen. J Immunol. 1996;156(1):128-135.

     [Crossref] [Google Scholar] [PubMed]

913. Higashi N, Fujioka K, Denda Nagai K, Hashimoto SI, Nagai S, Sato T, et al. The macrophage C-type lectin specific for galactose/N-acetylgalactosamine is an endocytic receptor expressed on monocyte-derived immature dendritic cells. J Biol Chem. 2002;277(23):20686-20693.

     [Crossref] [Google Scholar] [PubMed]

914. Beatson R, Maurstad G, Picco G, Arulappu A, Coleman J, Wandell HH, et al. The breast cancer-associated glycoforms of MUC1, MUC1-Tn and sialyl-Tn, are expressed in COSMC wild-type cells and bind the C-type lectin MGL. PloS one. 2015;10(5): e0125994.

     [Crossref] [Google Scholar] [PubMed]

915. Singh SK, Streng Ouwehand I, Litjens M, Weelij DR, García Vallejo JJ, van Vliet SJ, et al. Characterization of murine MGL1 and MGL2 C-type lectins: Distinct glycan specificities and tumor binding properties. Molecular immunology. 2009;46(6):1240-1249. 

     [Crossref] [Google Scholar] [PubMed]

916. Raes G, Brys L, Dahal BK, Brandt J, Grooten J, Brombacher F, et al. Macrophage galactose-type C-type lectins as novel markers for alternatively activated macrophages elicited by parasitic infections and allergic airway inflammation. J Leukoc Biol. 2005;77(3):321-327.

     [Crossref] [Google Scholar] [PubMed]

917. Pirro M, Rombouts Y, Stella A, Neyrolles O, Burlet Schiltz O, van Vliet SJ, et al. Characterization of Macrophage Galactose-type Lectin (MGL) ligands in colorectal cancer cell lines. Biochimica et Biophysica Acta (BBA)-General Subjects. 2020;1864(4):129513.

     [Crossref] [Google Scholar] [PubMed]

918. Mortezai N, Behnken HN, Kurze AK, Ludewig P, Buck F, Meyer B, et al. Tumor-associated Neu5Ac-Tn and Neu5Gc-Tn antigens bind to C-type lectin CLEC10A (CD301, MGL). Glycobiology. 2013;23(7):844-852.

     [Crossref] [Google Scholar] [PubMed]

919. van Vliet SJ, van Liempt E, Geijtenbeek TB, van Kooyk Y. Differential regulation of C-type lectin expression on tolerogenic dendritic cell subsets. Immunobiology. 2006;211(6-8):577-585.

     [Crossref] [Google Scholar] [PubMed]

920. Pace A, Scirocchi F, Napoletano C, Zizzari IG, D’Angelo L, Santoro A, et al. Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma. Int J Mol Sci. 2022;23(11):6312.

     [Crossref] [Google Scholar] [PubMed]

921. Rajesh C, Radhakrishnan P. The (Sialyl) Tn antigen: Contributions to immunosuppression in gastrointestinal cancers. Frontiers in Oncology. 2023; 12:1093496.

     [Crossref] [Google Scholar] [PubMed]

922. Dusoswa SA, Verhoeff J, Abels E, Méndez Huergo SP, Croci DO, Kuijper LH, et al. Glioblastomas exploit truncated O-linked glycans for local and distant immune modulation via the macrophage galactose-type lectin. Proc Natl Acad Sci U S A. 2020;117(7):3693-3703.

     [Crossref] [Google Scholar] [PubMed]

923. Rodriguez E, Boelaars K, Brown K, Madunić K, van Ee T, Dijk F, et al. Analysis of the glyco-code in pancreatic ductal adenocarcinoma identifies glycan-mediated immune regulatory circuits. Commun Biol. 2022;5(1):41.

     [Crossref] [Google Scholar] [PubMed]

924. Courtney AH, Amacher JF, Kadlecek TA, Mollenauer MN, Au Yeung BB, Kuriyan J, et al. A phosphosite within the SH2 domain of Lck regulates its activation by CD45. Mol Cell. 2017;67(3):498-511.

     [Crossref] [Google Scholar] [PubMed]

925. Courtney AH, Lo WL, Weiss A. TCR signaling: Mechanisms of initiation and propagation. Trends Biochem Sci. 2018;43(2):108-123.

     [Crossref] [Google Scholar] [PubMed]

926. van Vliet SJ, Gringhuis SI, Geijtenbeek TB, van Kooyk Y. Regulation of effector T cells by antigen-presenting cells via interaction of the C-type lectin MGL with CD45. Nat Immunol. 2006;7(11):1200-1208.

     [Crossref] [Google Scholar] [PubMed]

927. Zizzari IG, Martufi P, Battisti F, Rahimi H, Caponnetto S, Bellati F, et al. The macrophage galactose-type C-type lectin (MGL) modulates regulatory T cell functions. PLoS One. 2015;10(7): e0132617.

     [Crossref] [Google Scholar] [PubMed]

928. Van Vliet SJ, Vuist IM, Lenos K, Tefsen B, Kalay H, García Vallejo JJ, et al. Human T Cell activation results in extracellular signal-regulated kinase (erk)-calcineurin-dependent exposure of tn antigen on the cell surface and binding of the macrophage galactose-type lectin (mgl). J Biol Chem. 2013;288(38):27519-27532.

     [Crossref] [Google Scholar] [PubMed]

929. van Vliet SJ, Bay S, Vuist IM, Kalay H, García Vallejo JJ, Leclerc C, et al. MGL signaling augments TLR2-mediated responses for enhanced IL-10 and TNF-α secretion. J Leukoc Biol. 2013 ;94(2):315-323.

     [Crossref] [Google Scholar] [PubMed]

930. Napoletano C, Rughetti A, Agervig Tarp MP, Coleman J, Bennett EP, Picco G, et al. Tumor-associated Tn-MUC1 glycoform is internalized through the macrophage galactose-type C-type lectin and delivered to the HLA class I and II compartments in dendritic cells. Cancer Res. 2007;67(17):8358-8367.

     [Crossref] [Google Scholar] [PubMed]

931. Zizzari IG, Napoletano C, Battisti F, Rahimi H, Caponnetto S, Pierelli L, et al. MGL receptor and immunity: when the ligand can make the difference. J Immunol Res. 2015;2015(1):450695. 

     [Crossref] [Google Scholar] [PubMed]

932. Rughetti A, Pellicciotta I, Biffoni M, Bäckström M, Link T, Bennet EP, et al. Recombinant tumor-associated MUC1 glycoprotein impairs the differentiation and function of dendritic cells. J Immunol. 2005;174(12):7764-7772.

     [Crossref] [Google Scholar] [PubMed]

933. Szczykutowicz J. Ligand recognition by the macrophage galactose-type C-type lectin: Self or non-self? a way to trick the host’s immune system. Int J Mol Sci. 2023;24(23):17078.

     [Crossref] [Google Scholar] [PubMed]

934. Pirro M, Schoof E, van Vliet SJ, Rombouts Y, Stella A, de Ru A, et al. Glycoproteomic analysis of MGL-binding proteins on acute T-cell leukemia cells. J Proteome Res. 2018;18(3):1125-1132.

     [Crossref] [Google Scholar] [PubMed]

935. van Gisbergen KP, Aarnoudse CA, Meijer GA, Geijtenbeek TB, van Kooyk Y. Dendritic cells recognize tumor-specific glycosylation of carcinoembryonic antigen on colorectal cancer cells through dendritic cell–specific intercellular adhesion molecule-3–grabbing nonintegrin. Cancer Res. 2005;65(13):5935-5944.

     [Crossref] [Google Scholar] [PubMed]

936. Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y, et al. Identification of DC-SIGN, a novel dendritic cell–specific ICAM-3 receptor that supports primary immune responses.Cell. 2000;100(5):575-585.

     [Crossref] [Google Scholar] [PubMed]

937. Engering A, Geijtenbeek TB, van Vliet SJ, Wijers M, van Liempt E, Demaurex N, et al. The dendritic cell-specific adhesion receptor DC-SIGN internalizes antigen for presentation to T cells. J Immunol. 2002;168(5):2118-2126. 

     [Crossref] [Google Scholar] [PubMed]

938. Garcia Vallejo JJ, van Kooyk Y. The physiological role of DC-SIGN: A tale of mice and men. Trends Immunol. 2013;34(10):482-486.  

     [Crossref] [Google Scholar] [PubMed]

939. Geijtenbeek TB, Gringhuis SI. Signalling through C-type lectin receptors: Shaping immune responses. Nat Rev Immunol. 2009;9(7):465-479.

     [Crossref] [Google Scholar] [PubMed]

940. Gringhuis SI, Kaptein TM, Wevers BA, Van Der Vlist M, Klaver EJ, Van Die I, et al. Fucose-based PAMPs prime dendritic cells for follicular T helper cell polarization via DC-SIGN-dependent IL-27 production. Nat Commun. 2014;5(1):5074. 

     [Crossref] [Google Scholar] [PubMed]

941. Gringhuis SI, Den Dunnen J, Litjens M, Van Der Vlist M, Geijtenbeek TB. Carbohydrate-specific signaling through the DC-SIGN signalosome tailors immunity to Mycobacterium tuberculosis, HIV-1 and Helicobacter pylori. Nat Immunol. 2009;10(10):1081-1088.

     [Crossref] [Google Scholar] [PubMed]

942. Van Liempt E, Imberty A, Bank CM, Van Vliet SJ, Van Kooyk Y, Geijtenbeek TB, et al. Molecular basis of the differences in binding properties of the highly related C-type lectins DC-SIGN and L-SIGN to Lewis X trisaccharide and Schistosoma mansoni egg antigens. J Biol Chem.2004;279(32):33161-33167.

     [Crossref] [Google Scholar] [PubMed]

943. Pederson K, Mitchell DA, Prestegard JH. Structural characterization of the DC-SIGN–LewisX complex. Biochemistry. 2014;53(35):5700-5709. 

     [Crossref] [Google Scholar] [PubMed]

944. Soilleux EJ, Barten R, Trowsdale J. Cutting edge: DC-SIGN; a related gene, DC-SIGNR; and CD23 form a cluster on 19p13. J Immunol. 2000;165(6):2937-2942. 

     [Crossref] [Google Scholar] [PubMed]

945. Granelli-Piperno A, Pritsker A, Pack M, Shimeliovich I, Arrighi JF, Park CG, et al. Dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin/CD209 is abundant on macrophages in the normal human lymph node and is not required for dendritic cell stimulation of the mixed leukocyte reaction. J Immunol. 2005;175(7):4265-4273.

     [Crossref] [Google Scholar] [PubMed]

946. Dominguez Soto A, Sierra Filardi E, Puig Kröger A, Pérez Maceda B, Gómez Aguado F, Corcuera MT, et al. Dendritic cell-specific ICAM-3–grabbing nonintegrin expression on M2-polarized and tumor-associated macrophages is macrophage-CSF dependent and enhanced by tumor-derived IL-6 and IL-10. J Immunol. 2011;186(4):2192-2200.

     [Crossref] [Google Scholar] [PubMed]

947. Hu B, Wang Z, Zeng H, Qi Y, Chen Y, Wang T, et al. Blockade of DC-SIGN+ tumor-associated macrophages reactivates antitumor immunity and improves immunotherapy in muscle-invasive bladder cancer. Cancer Res. 2020;80(8):1707-1719. 

     [Crossref] [Google Scholar] [PubMed]

948. van Gisbergen KP, Aarnoudse CA, Meijer GA, Geijtenbeek TB, van Kooyk Y. Dendritic cells recognize tumor-specific glycosylation of carcinoembryonic antigen on colorectal cancer cells through dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin. Cancer Res. 2005;65:5935–5944.

     [Crossref] [Google Scholar] [PubMed]

949. Nonaka M, Ma BY, Murai R, Nakamura N, Baba M, Kawasaki N, et al. Glycosylation-dependent interactions of C-type lectin DC-SIGN with colorectal tumor-associated Lewis glycans impair the function and differentiation of monocyte-derived dendritic cells. J Immunol. 2008;180(5):3347-3356.

     [Crossref] [Google Scholar] [PubMed]

950. Gijzen K, Raymakers RA, Broers KM, Figdor CG, Torensma R. Interaction of acute lymphopblastic leukemia cells with C-type lectins DC-SIGN and L-SIGN. Exp Hematol. 2008;36(7):860-870.

     [Crossref] [Google Scholar] [PubMed]

951. Hu B, Wang Z, Zeng H, Qi Y, Chen Y, Wang T, et al. Blockade of DC-SIGN+ tumor-associated macrophages reactivates antitumor immunity and improves immunotherapy in muscle-invasive bladder cancer. Cancer Res. 2020;80(8):1707-1719.

     [Crossref] [Google Scholar] [PubMed]

952. Haebe S, Day G, Czerwinski DK, Sathe A, Grimes SM, Chen T, et al. Follicular lymphoma evolves with a surmountable dependency on acquired glycosylation motifs in the B-cell receptor. Blood. 2023;142(26):2296-2304.

     [Crossref] [Google Scholar] [PubMed]

953. Veelken H. Energy overpowers sweet tooth in FL. Blood. 2023;142(26):2226-2229.

     [Crossref] [Google Scholar] [PubMed]

954. Amin R, Mourcin F, Uhel F, Pangault C, Ruminy P, Dupré L, et al. DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma. Blood. 2015;126(16):1911-1920.

     [Crossref] [Google Scholar] [PubMed]

955. Koning MT, Quinten E, Zoutman WH, Kiełbasa SM, Mei H, van Bergen CA, et al. Acquired N-linked glycosylation motifs in B-cell receptors of primary cutaneous B-cell lymphoma and the normal B-cell repertoire. J Invest Dermatol. 2019;139(10):2195-2203.

     [Crossref] [Google Scholar] [PubMed]

956. Schneider D, Dühren von Minden M, Alkhatib A, Setz C, van Bergen CA, Benkißer Petersen M, et al. Lectins from opportunistic bacteria interact with acquired variable-region glycans of surface immunoglobulin in follicular lymphoma. Blood. 2015;125(21):3287-3296.

     [Crossref] [Google Scholar] [PubMed]

957. Hollander N, Haimovich J. Altered N-linked glycosylation in follicular lymphoma and chronic lymphocytic leukemia: involvement in pathogenesis and potential therapeutic targeting. Front Immunol. 2017;8:912.

     [Crossref] [Google Scholar] [PubMed]

958. Zhao X, Singh S, Pardoux C, Zhao J, Hsi ED, Abo A, et al. Targeting C-type lectin-like molecule-1 for antibody-mediated immunotherapy in acute myeloid leukemia. Haematologica. 2010;95(1):71.

     [Crossref] [Google Scholar] [PubMed]

959. Laborda E, Mazagova M, Shao S, Wang X, Quirino H, Woods AK, Hampton EN, Rodgers DT, Kim CH, Schultz PG, Young TS. Development of a chimeric antigen receptor targeting C-type lectin-like molecule-1 for human acute myeloid leukemia. Int J Mol Sci. 2017;18(11):2259.

     [Crossref] [Google Scholar] [PubMed]

960. Julien S, Ivetic A, Grigoriadis A, QiZe D, Burford B, Sproviero D, et al. Selectin ligand sialyl-Lewis x antigen drives metastasis of hormone-dependent breast cancers. Cancer Res. 2011;71(24):7683-7693.

     [Crossref] [Google Scholar] [PubMed]

961. Arbones ML, Ord DC, Ley K, Ratech H, Maynard Curry C, Otten G, et al. Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectin-deficient mice. Immunity. 1994;1(4):247-260.

     [Crossref] [Google Scholar] [PubMed]

962. Austrup F, Vestweber D, Borges E, Löhning M, Bräuer R, Herz U, et al. P-and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature. 1997;385(6611):81-83.

     [Crossref] [Google Scholar] [PubMed]

963. Ley K. The role of selectins in inflammation and disease. Trends Mol Med. 2003;9(6):263-268.

     [Crossref] [Google Scholar] [PubMed]

964. Subramaniam M, Koedam JA, Wagner DD. Divergent fates of P-and E-selectins after their expression on the plasma membrane. Mol Biol Cel. 1993;4(8):791-801.

     [Crossref] [Google Scholar] [PubMed]

965. Ellies LG, Sperandio M, Underhill GH, Yousif J, Smith M, Priatel JJ, et al. Sialyltransferase specificity in selectin ligand formation. Blood. 2002;100(10):3618-3625.

     [Crossref] [Google Scholar] [PubMed]

966. Sperandio M, Gleissner CA, Ley K. Glycosylation in immune cell trafficking. Immunol Rev. 2009; 230(1):97-113.

     [Crossref] [Google Scholar] [PubMed]

967. Ivetic A, Hoskins Green HL, Hart SJ. L-selectin: A major regulator of leukocyte adhesion, migration and signaling. Front Immunol. 2019;10:1068.

     [Crossref] [Google Scholar] [PubMed]

968. Hirata T. Blood Vascular Endothelial Adhesion Molecules.
969. Blanchard L, Girard JP. High endothelial Venules (HEVs) in immunity, inflammation and cancer. Angiogenesis. 2021;24(4):719-753.

     [Crossref] [Google Scholar] [PubMed]

970. Kawashima H, Petryniak B, Hiraoka N, Mitoma J, Huckaby V, Nakayama J, et al. N-acetylglucosamine-6-O-sulfotransferases 1 and 2 cooperatively control lymphocyte homing through L-selectin ligand biosynthesis in high endothelial venules. Nat Immunol. 2005;6(11):1096-1104.

     [Crossref] [Google Scholar] [PubMed]

971. Mitsuoka C, Sawada Kasugai M, Ando Furui K, Izawa M, Nakanishi H, Nakamura S, et al. Identification of a major carbohydrate capping group of the L-selectin ligand on high endothelial venules in human lymph nodes as 6-sulfo sialyl Lewis X. J Biol Chem. 1998; 273(18):11225-11233.

     [Crossref] [Google Scholar] [PubMed]

972. Mitoma J, Bao X, Petryanik B, Schaerli P, Gauguet JM, Yu SY, et al. Critical functions of N-glycans in L-selectin-mediated lymphocyte homing and recruitment. Nat Immunol.2007;8(4):409-418.

     [Crossref] [Google Scholar] [PubMed]

973. Trinchera M, Aronica A, Dall’Olio F. Selectin ligands Sialyl-Lewis a and Sialyl-Lewis x in gastrointestinal cancers. Biology. 2017; 6(1):16.

     [Crossref] [Google Scholar] [PubMed]

974. Leppänen A, Parviainen V, Ahola-Iivarinen E, Kalkkinen N, Cummings RD. Human L-selectin preferentially binds synthetic glycosulfopeptides modeled after endoglycan and containing tyrosine sulfate residues and sialyl Lewis x in core 2 O-glycans. Glycobiology. 2010;20(9):1170-1185.

     [Crossref] [Google Scholar] [PubMed]

975. Galustian C, Lawson AM, Komba S, Ishida H, Kiso M, Feizi T. Sialyl-lewisxsequence 6-o-sulfated atn-acetylglucosamine rather than at galactose is the preferred ligand forl-selectin and de-n-acetylation of the sialic acid enhances the binding strength. Biochem Biophys Res Commun. 1997;240(3):748-751.

     [Crossref] [Google Scholar] [PubMed]

976. Chen Q, Liu H, Li X. Essential functions, syntheses and detection of sialyl Lewis X on glycoproteins. EDS. 2023.

     [Crossref] [Google Scholar]

977. Streeter PR, Rouse BT, Butcher EC. Immunohistologic and functional characterization of a vascular addressin involved in lymphocyte homing into peripheral lymph nodes. J Cell Biol. 1988;107(5):1853-1862.

     [Crossref] [Google Scholar] [PubMed]

978. Michie SA, Streeter PR, Bolt PA, Butcher EC, Picker LJ. The human peripheral lymph node vascular addressin. An inducible endothelial antigen involved in lymphocyte homing. Am J Pathol. 1993;143(6):1688.

     [Google Scholar] [PubMed]

979. Yeh JC, Hiraoka N, Petryniak B, Nakayama J, Ellies LG, Rabuka D, et al. Novel sulfated lymphocyte homing receptors and their control by a Core1 extension β1, 3-N-acetylglucosaminyltransferase.Cell. 2001;105(7):957-969.

     [Crossref] [Google Scholar] [PubMed]

980. Hobbs SJ, Nolz JC. Regulation of T cell trafficking by enzymatic synthesis of O-glycans. Front Immunol. 2017;8:600.

     [Crossref] [Google Scholar] [PubMed]

981. Goth CK, Mehta AY, McQuillan AM, Baker KJ, Hanes MS, Park SS, et al. Chemokine binding to PSGL-1 is controlled by O-glycosylation and tyrosine sulfation. Cell Chem Biol. 2023;30(8):893-905.

     [Crossref] [Google Scholar] [PubMed]

982. Leppänen A, Mehta P, Ouyang YB, Ju T, Helin J, Moore KL, et al. A novel glycosulfopeptide binds to P-selectin and inhibits leukocyte adhesion to P-selectin. J Biol Chem. 1999;274(35):24838-24848. 

     [Crossref] [Google Scholar] [PubMed]

983. Somers WS, Tang J, Shaw GD, Camphausen RT. Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P-and E-selectin bound to SLeX and PSGL-1.Cell.2000;103(3):467-479.

     [Crossref] [Google Scholar] [PubMed]

984. Kanamori A, Kojima N, Uchimura K, Muramatsu T, Tamatani T, Berndt MC, et al. Distinct sulfation requirements of selectins disclosed using cells that support rolling mediated by all three selectins under shear flow: L-selectin prefers carbohydrate 6-sulfation to tyrosine sulfation, whereas p-selectin does not. J Biol Chem. 2002;277(36):32578-32586.

     [Crossref] [Google Scholar] [PubMed]

985. Florena AM, Tripodo C, Miceli L, Ingrao S, Porcasi R, Franco V. Identification of CD162 in plasma-cell dyscrasia. Lancet Oncol. 2005;6(8):632.

     [Crossref] [Google Scholar] [PubMed]

986. Muz B, Azab F, De La Puente P, Rollins S, Alvarez R, Kawar Z, et al. Inhibition of P‐selectin and PSGL‐1 using humanized monoclonal antibodies increases the sensitivity of multiple myeloma cells to bortezomib. Biomed Res Int. 2015;2015(1):417586.

     [Crossref] [Google Scholar] [PubMed]

987. Raes G, Ghassabeh GH, Brys L, Mpofu N, Verschueren H, Vanhecke D, et al. The metastatic T‐cell hybridoma antigen/P‐selectin glycoprotein ligand 1 is required for hematogenous metastasis of lymphomas. Int J Cancer. 2007;121(12):2646-2652.

     [Crossref] [Google Scholar] [PubMed]

988. Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019;574(7779):565-570.

     [Crossref] [Google Scholar] [PubMed]

989. DeRogatis JM, Viramontes KM, Neubert EN, Tinoco R. PSGL-1 immune checkpoint inhibition for CD4+ T cell cancer immunotherapy. Front Immunol. 2021; 12:636238.

     [Crossref] [Google Scholar] [PubMed]

990. Tagliamento M, Bironzo P, Novello S. New emerging targets in cancer immunotherapy: The role of VISTA. ESMO Open. 2019;4: e000683.

     [Crossref] [Google Scholar] [PubMed]

991. Kansas GS. Selectins and their ligands: Current concepts and controversies. Blood.1996;88(9):3259-3287.

     [Google Scholar] [PubMed]

992. Hill CA. Interactions between endothelial selectins and cancer cells regulate metastasis. Front Biosci. 2011;16(8):3233-3251.

     [Crossref] [Google Scholar] [PubMed]

993. Zhong L, Simoneau B, Tremblay PL, Gout S, Simard MJ, Huot J. E-selectin-mediated adhesion and extravasation in cancer. Encycl Cancer. 2014:1618-1624.

     [Google Scholar]

994. Price TT, Burness ML, Sivan A, Warner MJ, Cheng R, Lee CH, et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone. Sci Transl Med. 2016;8(340):340ra73.

     [Crossref] [Google Scholar] [PubMed]

995. Esposito M, Mondal N, Greco TM, Wei Y, Spadazzi C, Lin SC, et al. Bone vascular niche E-selectin induces mesenchymal–epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat Cell Biol. 2019;21(5):627-639.

     [Crossref] [Google Scholar] [PubMed]

996. Connolly C, Jha A, Natoni A, O'Dwyer ME. A 13-glycosylation gene signature in multiple myeloma can predicts survival and identifies candidates for targeted therapy (GiMM13). Blood. 2016;128(22):4423.

     [Crossref] [Google Scholar]

997. Lowe JB. Glycan-dependent leukocyte adhesion and recruitment in inflammation. Curr Opin Cell Biol. 2003;15(5):531-538.

     [Crossref] [Google Scholar] [PubMed]

998. Läubli H, Borsig L. Selectins as mediators of lung metastasis. Cancer Microenviron. 2010; 3:97-105.

     [Crossref] [Google Scholar] [PubMed]

999. Fabricius HÅ, Starzonek S, Lange T. The role of platelet cell surface P-selectin for the direct platelet-tumor cell contact during metastasis formation in human tumors. Front Oncol. 2021; 11:642761.

     [Crossref] [Google Scholar] [PubMed]

1000. Läubli H, Borsig L. Heparins attenuate cancer metastasis: Are selectins the link? Cancer Invest. 2009;27(5):474-481.

      [Crossref] [Google Scholar] [PubMed]

1001. Ludwig RJ, Schön MP, Boehncke WH. P-selectin: A common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis. Expert Opin Ther Targets. 2007;11(8):1103-1117.  

      [Crossref] [Google Scholar] [PubMed]

1002. Rabinovich GA, Toscano MA. Turning'sweet'on immunity: Galectin–glycan interactions in immune tolerance and inflammation. Nat Rev Immunol. 2009;9(5):338-352.

      [Crossref] [Google Scholar] [PubMed]

1003. Vasta GR. Galectins as pattern recognition receptors: Structure, function, and evolution. Adv Exp Med Biol. 2012; 946:21-36.

      [Crossref] [Google Scholar] [PubMed]

1004. Hirabayashi J, Hashidate T, Arata Y, Nishi N, Nakamura T, Hirashima M, et al. Oligosaccharide specificity of galectins: A search by frontal affinity chromatography. Biochim Biophys Acta. 2002;1572(2-3):232-254.

      [Crossref] [Google Scholar] [PubMed]

1005. Guha P, Kaptan E, Bandyopadhyaya G, Kaczanowska S, Davila E, Thompson K, et al. Cod glycopeptide with picomolar affinity to galectin-3 suppresses T-cell apoptosis and prostate cancer metastasis. Proc Natl Acad Sci USA. 2013;110(13):5052-5057.

      [Crossref] [Google Scholar] [PubMed]

1006. Ahmed H, Fink NE, Pohl J, Vasta GR. Galectin-1 from bovine spleen: Biochemical characterization, carbohydrate specificity and tissue-specific isoform profiles. J Biochem. 1996;120(5):1007-1019.

      [Crossref] [Google Scholar] [PubMed]

1007. Ideo H, Matsuzaka T, Nonaka T, Seko A, Yamashita K. Galectin-8-N-domain recognition mechanism for sialylated and sulfated glycans. J Biol Chem. 2011;286(13):11346-11355.

      [Crossref] [Google Scholar] [PubMed]

1008. Stowell SR, Arthur CM, Mehta P, Slanina KA, Blixt O, Leffler H, et. al. Galectin-1,-2, and-3 exhibit differential recognition of sialylated glycans and blood group antigens. J Biol Chem. 2008;283(15):10109-10123.

      [Crossref] [Google Scholar] [PubMed]

1009. Patnaik SK, Potvin B, Carlsson S, Sturm D, Leffler H, Stanley P. Complex N-glycans are the major ligands for galectin-1,-3, and-8 on Chinese hamster ovary cells. Glycobiology. 2006;16(4):305-317.

      [Crossref] [Google Scholar] [PubMed]

1010. Troncoso MF, Elola MT, Blidner AG, Sarrias L, Espelt MV, Rabinovich GA. The universe of galectin-binding partners and their functions in health and disease. J Biol Chem. 2023;299(12):105400.

      [Crossref] [Google Scholar] [PubMed]

1011. Johannes L, Jacob R, Leffler H. Galectins at a glance. J Cell Sci. 2018;131(9):208884.

      [Crossref] [Google Scholar] [PubMed]

1012. Schnaar RL. Glycans and glycan-binding proteins in immune regulation: A concise introduction to glycobiology for the allergist. J Allergy Clin Immunol. 2015;135(3):609-615.

      [Crossref] [Google Scholar] [PubMed]

1013. Vladoiu MC, Labrie M, St-Pierre Y. Intracellular galectins in cancer cells: Potential new targets for therapy. Int J Oncol. 2014;44(4):1001-1014.

      [Crossref] [Google Scholar] [PubMed]

1014. Troncoso MF, Elola MT, Croci DO, Rabinovich GA. Integrating structure and function of ‘tandem-repeat’galectins. Front Biosci (Schol Ed). 2012;4(3):864-887.

      [Crossref] [Google Scholar] [PubMed]

1015. Haudek KC, Spronk KJ, Voss PG, Patterson RJ, Wang JL, Arnoys EJ. Dynamics of galectin-3 in the nucleus and cytoplasm. Biochim Biophys Acta. 2010;1800(2):181-189.

      [Crossref] [Google Scholar] [PubMed]

1016. Brewer CF. Binding and cross-linking properties of galectins. Biochim Biophys Acta. 2002;1572(2-3):255-262.

      [Crossref] [Google Scholar] [PubMed]

1017. Garner OB, Baum LG. Galectin–glycan lattices regulate cell-surface glycoprotein organization and signalling. Biochem Soc Trans. 2008;36(6):1472-1477.

      [Crossref] [Google Scholar] [PubMed]

1018. Garner OB, Baum LG. Galectin–glycan lattices regulate cell-surface glycoprotein organization and signalling. Biochem Soc Trans. 2008;36(6):1472-1477.

      [Crossref] [Google Scholar] [PubMed]

1019. Abbott KL, Matthews RT, Pierce M. Receptor Tyrosine Phosphatase β (RPTPβ) activity and signaling are attenuated by glycosylation and subsequent cell surface galectin-1 binding. J Biol Chem. 2008;283(48):33026-33035.

      [Crossref] [Google Scholar] [PubMed]

1020. Suzuki O. Regulation of cell adhesion to galectins by glycosylation: A new concept in lymphoma cell adhesion. Adv Cancer Biol-Metastasis. 2021;3:100016.

      [Crossref] [Google Scholar]

1021. Compagno D, Tiraboschi C, Garcia JD, Rondón Y, Corapi E, Velazquez C, et al. Galectins as checkpoints of the immune system in cancers, their clinical relevance, and implication in clinical trials. Biomolecules. 2020;10(5):750.

      [Crossref] [Google Scholar] [PubMed]

1022. Elola MT, Ferragut F, Mendez Huergo SP, Croci DO, Bracalente C, Rabinovich GA. Galectins: Multitask signaling molecules linking fibroblast, endothelial and immune cell programs in the tumor microenvironment. Cell Immunol. 2018; 333:34-45.

      [Crossref] [Google Scholar] [PubMed]

1023. Liu FT, Rabinovich GA. Galectins as modulators of tumour progression. Nat Rev Cancer. 2005;5(1):29-41.

      [Crossref] [Google Scholar] [PubMed]

1024. Modenutti CP, Capurro JI, Di Lella S, Marti MA. The structural biology of galectin-ligand recognition: Current advances in modeling tools, protein engineering, and inhibitor design. Front Chem. 2019;7:823.

      [Crossref] [Google Scholar] [PubMed]

1025. Mereiter S, Balmaña M, Campos D, Gomes J, Reis CA. Glycosylation in the era of cancer-targeted therapy: Where are we heading? Cancer cell. 2019;36(1):6-16.

      [Crossref] [Google Scholar] [PubMed]

1026. Porębska N, Pozniak M, Matynia A, Zukowska D, Zakrzewska M, Otlewski J, et al. Galectins as modulators of receptor tyrosine kinases signaling in health and disease. Cytokine Growth Factor Rev. 2021; 60:89-106.

      [Crossref] [Google Scholar] [PubMed]

1027. Funkhouser A, Shuster H, Martin JC, Edenfield WJ, Blenda AV. Pattern analysis of serum galectins-1,-3, and-9 in breast cancer. Cancers (Basel). 2023;15(15):3809.

      [Crossref] [Google Scholar] [PubMed]

1028. Abroun S, Otsuyama KI, Shamsasenjan K, Islam A, Amin J, Iqbal MS, Gondo T, et al. Galectin‐1 supports the survival of CD45RA (−) primary myeloma cells in vitro. Br J Haematol. 2008;142(5):754-765.

      [Crossref] [Google Scholar] [PubMed]

1029. Storti P, Marchica V, Airoldi I, Donofrio G, Fiorini E, Ferri V, et al. Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo. Leukemia. 2016;30(12):2351-2363.

      [Crossref] [Google Scholar] [PubMed]

1030. Croci DO, Morande PE, Dergan-Dylon S, Borge M, Toscano MA, Stupirski JC, et al. Nurse-like cells control the activity of chronic lymphocytic leukemia B cells via galectin-1. Leukemia. 2013;27(6):1413-1416.

      [Crossref] [Google Scholar] [PubMed]

1031. Pena C, Mirandola L, Figueroa JA, Hosiriluck N, Suvorava N, Trotter K, et al. Galectins as therapeutic targets for hematological malignancies: A hopeful sweetness. Ann Transl Med. 2014;2(9):87.

      [Crossref] [Google Scholar] [PubMed]

1032. Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J, et al. The AP1-dependent secretion of galectin-1 by Reed–Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci U S A. 2007;104(32):13134-13139.

      [Crossref] [Google Scholar] [PubMed]

1033. Kamper P, Ludvigsen M, Bendix K, Hamilton-Dutoit S, Rabinovich GA, Moller MB, et al. Proteomic analysis identifies galectin-1 as a predictive biomarker for relapsed/refractory disease in classical Hodgkin lymphoma. Blood. 2011;117(24):6638-6649.

      [Crossref] [Google Scholar] [PubMed]

1034. Ouyang J, Plutschow A, Von Strandmann EP, Reiners KS, Ponader S, Rabinovich GA, et al. Galectin-1 serum levels reflect tumor burden and adverse clinical features in classical Hodgkin lymphoma. Blood. 2013;121(17):3431-3433.

      [Crossref] [Google Scholar] [PubMed]

1035. Oliveira T, Zhang M, Joo EJ, Abdel-Azim H, Chen CW, Yang L, et al. Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia. Theranostics. 2021;11(19):9519.

      [Crossref] [Google Scholar] [PubMed]

1036. Paz H, Joo EJ, Chou CH, Fei F, Mayo KH, Abdel-Azim H, et al. Treatment of B-cell precursor acute lymphoblastic leukemia with the Galectin-1 inhibitor PTX008. J Exp Clin Cancer Res. 2018;37(1):1-5.

      [Crossref] [Google Scholar] [PubMed]

1037. Cedeno-Laurent F, Watanabe R, Teague JE, Kupper TS, Clark RA, Dimitroff CJ. Galectin-1 inhibits the viability, proliferation, and Th1 cytokine production of nonmalignant T cells in patients with leukemic cutaneous T-cell lymphoma. Blood,. 2012;119(15):3534-3538.

      [Crossref] [Google Scholar] [PubMed]

1038. Ruvolo PP, Ruvolo VR, Burks JK, Qiu Y, Wang RY, Shpall EJ, et al. Role of MSC-derived galectin 3 in the AML microenvironment. Biochim Biophys Acta Mol Cell Res. 2018;1865(7):959-969.

      [Crossref] [Google Scholar] [PubMed]

1039. Ruvolo PP, Ruvolo VR, Benton CB, AlRawi A, Burks JK, Schober W, et al. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells. Biochim Biophys Acta. 2016;1863(4):562-571.

      [Crossref] [Google Scholar] [PubMed]

1040. Nakayama R, Kuroda J, Taniyama N, Yamamoto-Sugitani M, Wada S, Kiyota M, et al. Suppression of SERPINA1-albumin complex formation by galectin-3 overexpression leads to paracrine growth promotion of chronic myelogenous leukemia cells. Leuk Res. 2014;38(1):103-108.

      [Crossref] [Google Scholar] [PubMed]

1041. Yamamoto-Sugitani M, Kuroda J, Ashihara E, Nagoshi H, Kobayashi T, Matsumoto Y, et al. Galectin-3 (Gal-3) induced by leukemia microenvironment promotes drug resistance and bone marrow lodgment in chronic myelogenous leukemia. Proc Natl Acad Sci U S A. 2011;108(42):17468-17473.

      [Crossref] [Google Scholar] [PubMed]

1042. Fei F, Joo EJ, Tarighat SS, Schiffer I, Paz H, Fabbri M, et al. B-cell precursor acute lymphoblastic leukemia and stromal cells communicate through Galectin-3. Oncotarget. 2015;6(13):11378-11394.

      [Crossref] [Google Scholar] [PubMed]

1043. Storti P, Marchica V, Giuliani N. Role of galectins in multiple myeloma. Int J Mol Sci. 2017;18(12):2740.

      [Crossref] [Google Scholar] [PubMed]

1044. Clark MC, Pang M, Hsu DK, Liu FT, de Vos S, Gascoyne RD, et al. Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death. Blood. 2012;120(23):4635-4644.

      [Crossref] [Google Scholar] [PubMed]

1045. Kobayashi T, Kuroda J, Ashihara E, Oomizu S, Terui Y, Taniyama A, et al. Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways. Leukemia. 2010;24(4):843-850.

      [Crossref] [Google Scholar] [PubMed]

1046. Silva IG, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. EBioMedicine. 2017;22:44-57.

      [Crossref] [Google Scholar] [PubMed]

1047. Günther J, Galuska SP. A brief history of galectin evolution. Front Immunol. 2023; 14:1147356.

      [Crossref] [Google Scholar] [PubMed]

1048. Liu FT, Stowell SR. The role of galectins in immunity and infection. Nat Rev Immunol. 2023;23(8):479-494.

      [Crossref] [Google Scholar] [PubMed]

1049. de Waard AD, Hickman SC, Kornfeld ST. Isolation and properties of beta-galactoside binding lectins of calf heart and lung. J Biol Chem. 1976;251(23):7581-7587.

      [Crossref] [Google Scholar] [PubMed]

1050. Dias-Baruffi M, Stowell SR, Song SC, Arthur CM, Cho M, Rodrigues LC, et al. Differential expression of immunomodulatory galectin-1 in peripheral leukocytes and adult tissues and its cytosolic organization in striated muscle. Glycobiology. 2010;20(5):507-520.

      [Crossref] [Google Scholar] [PubMed]

1051. Chen X, Song CH, Liu ZQ, Feng BS, Zheng PY, Li P, et al. Intestinal epithelial cells express galectin‐9 in patients with food allergy that plays a critical role in sustaining allergic status in mouse intestine. Allergy. 2011;66(8):1038-1046.

      [Crossref] [Google Scholar] [PubMed]

1052. Wada J, Ota K, Kumar A, Wallner EI, Kanwar YS. Developmental regulation, expression, and apoptotic potential of galectin-9, a beta-galactoside binding lectin. J Clin Invest. 1997;99(10):2452-2461.

      [Crossref] [Google Scholar] [PubMed]

1053. Imaizumi T, Kumagai M, Sasaki N, Kurotaki H, Mori F, Seki M, et al. Interferon-γ stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol. 2002;72(3):486-491.

      [Crossref] [Google Scholar] [PubMed]

1054. Girotti MR, Salatino M, Dalotto-Moreno T, Rabinovich GA. Sweetening the hallmarks of cancer: Galectins as multifunctional mediators of tumor progression. J Exp Med. 2019;217(2):20182041.

      [Crossref] [Google Scholar] [PubMed]

1055. Rabinovich GA, Baum LG, Tinari N, Paganelli R, Natoli C, Liu FT, et al. Galectins and their ligands: Amplifiers, silencers or tuners of the inflammatory response? Trends Immunol. 2002;23(6):313-320.

      [Crossref] [Google Scholar] [PubMed]

1056. Hubbard SC, Kranz DM, Longmore GD, Sitkovsky MV, Eisen HN. Glycosylation of the T-cell antigen-specific receptor and its potential role in lectin-mediated cytotoxicity. Proc Natl Acad Sci U S A. 1986;83(6):1852-1856.

      [Crossref] [Google Scholar] [PubMed]

1057. Grigorian A, Torossian S, Demetriou M. T‐cell growth, cell surface organization, and the galectin–glycoprotein lattice. Immunol Rev. 2009;230(1):232-246.

      [Crossref] [Google Scholar] [PubMed]

1058. Sun ZY, Kim ST, Kim IC, Fahmy A, Reinherz EL, Wagner G. Solution structure of the CD3εδ ectodomain and comparison with CD3εγ as a basis for modeling T cell receptor topology and signaling. Proc Natl Acad Sci U S A. 2004;101(48):16867-16872.

      [Crossref] [Google Scholar] [PubMed]

1059. Lhuillier C, Barjon C, Niki T, Gelin A, Praz F, Morales O, et al. Impact of exogenous galectin-9 on human T cells: Contribution of the T cell receptor complex to antigen-independent activation but not to apoptosis induction. J Biol Chem. 2015;290(27):16797-16811.

      [Crossref] [Google Scholar] [PubMed]

1060. Selnø AT. Biochemical Regulation of the Tim-3-Galectin-9 Immunosuppressive Pathway under Normal Conditions and upon Cell Malignant Transformation. University of Kent (United Kingdom).2021.

      [Crossref] [Google Scholar]

1061. Mantuano NR, Natoli M, Zippelius A, Laubli H. Tumor-associated carbohydrates and immunomodulatory lectins as targets for cancer immunotherapy. J Immunother Cancer. 2020;8(2):001222.

      [Crossref] [Google Scholar] [PubMed]

1062. Curti BD, Koguchi Y, Leidner RS, Rolig AS, Sturgill ER, Sun Z, et al. Enhancing clinical and immunological effects of anti-PD-1 with belapectin, a galectin-3 inhibitor. J Immunother Cance. 2021;9(4):002371.

      [Crossref] [Google Scholar] [PubMed]

1063. Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun. 2021;12(1):832.

      [Crossref] [Google Scholar] [PubMed]

1064. Wu X, Giobbie-Hurder A, Connolly EM, Li J, Liao X, Severgnini M, et al. Anti-CTLA-4 based therapy elicits humoral immunity to galectin-3 in patients with metastatic melanoma. Oncoimmunology. 2018;7(7):1440930.

      [Crossref] [Google Scholar] [PubMed]

1065. Gilson RC, Gunasinghe SD, Johannes L, Gaus K. Galectin-3 modulation of T-cell activation: Mechanisms of membrane remodelling. Prog Lipid Res. 2019; 76:101010.

      [Crossref] [Google Scholar] [PubMed]

1066. Kouo T, Huang L, Pucsek AB, Cao M, Solt S, Armstrong T, et al. Galectin-3 shapes antitumor immune responses by suppressing CD8+ T cells via LAG-3 and inhibiting expansion of plasmacytoid dendritic cells. Cancer Immunol Res. 2015;3(4):412-423. 

      [Crossref] [Google Scholar] [PubMed]

1067. He Y, Rivard CJ, Rozeboom L, Yu H, Ellison K, Kowalewski A, et al. Lymphocyte‐activation gene‐3, an important immune checkpoint in cancer. Cancer Sci. 2016;107(9):1193-1197.

      [Crossref] [Google Scholar] [PubMed]

1068. Andrews LP, Marciscano AE, Drake CG, Vignali DA. LAG 3 (CD 223) as a cancer immunotherapy target. Immunol Rev. 2017;276(1):80-96.

      [Crossref] [Google Scholar] [PubMed]

1069. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6(12):1245-1252.

      [Crossref] [Google Scholar] [PubMed]

1070. Chongsaritsinsuk J, Steigmeyer AD, Mahoney KE, Rosenfeld MA, Lucas TM, Smith CM, et al. Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE. Nat Commun. 2023;14(1):6169.

      [Crossref] [Google Scholar] [PubMed]

1071. Kandel S, Adhikary P, Li G, Cheng K. The TIM3/Gal9 signaling pathway: An emerging target for cancer immunotherapy. Cancer Lett. 2021; 510:67-78.

      [Crossref] [Google Scholar] [PubMed]

1072. Cagnoni AJ, Giribaldi ML, Blidner AG, Cutine AM, Gatto SG, Morales RM, et al. Galectin-1 fosters an immunosuppressive microenvironment in colorectal cancer by reprogramming CD8+ regulatory T cells. Proc Natl Acad Sci. 2021;118(21):e2102950118.

      [Crossref] [Google Scholar] [PubMed]

1073. Videla-Richardson GA, Morris-Hanon O, Torres NI, Esquivel MI, Vera MB, Ripari LB, et al. Galectins as emerging glyco-checkpoints and therapeutic targets in glioblastoma. Int J Mol Sci. 2021;23(1):316.

      [Crossref] [Google Scholar] [PubMed]

1074. Ebrahim AH, Alalawi Z, Mirandola L, Rakhshanda R, Dahlbeck S, Nguyen D, et al. Galectins in cancer: carcinogenesis, diagnosis and therapy. Ann Trans Med. 2014;2(9).

      [Crossref] [Google Scholar] [PubMed]

1075. Cedeno-Laurent F, Dimitroff CJ. Galectin-1 research in T cell immunity: past, present and future. Clin Immunol. 2012;142(2):107-116.

      [Crossref] [Google Scholar] [PubMed]

1076. Tiraboschi C, Gentilini L, Velazquez C, Corapi E, Jaworski FM, Garcia JD, et al. Combining inhibition of galectin-3 with and before a therapeutic vaccination is critical for the prostate-tumor-free outcome. J Immunother Cancer. 2020;8(2).

      [Crossref] [Google Scholar] [PubMed]

1077. Nakajima K, Balan V, Raz A. Galectin-3: An immune checkpoint target for musculoskeletal tumor patients. Cancer Metastasis Rev. 2021;40(1):297-302.

      [Crossref] [Google Scholar] [PubMed]

1078. Li E, Xu J, Chen Q, Zhang X, Xu X, Liang T. Galectin-9 and PD-L1 antibody blockade combination therapy inhibits tumour progression in pancreatic cancer. Immunotherapy. 2023;15(3):135-47.

      [Crossref] [Google Scholar] [PubMed]

1079. Ingrassia L, Nshimyumukiza P, Dewelle J, Lefranc F, Wlodarczak L, Thomas S, Dielie G, et al. A lactosylated steroid contributes in vivo therapeutic benefits in experimental models of mouse lymphoma and human glioblastoma. J Med Chem. 2006;49(5):1800-1807.

      [Crossref] [Google Scholar] [PubMed]

1080. Ingrassia L, Nshimyumukiza P, Dewelle J, Lefranc F, Wlodarczak L, Thomas S, et al. A lactosylated steroid contributes in vivo therapeutic benefits in experimental models of mouse lymphoma and human glioblastoma. J Med Chem. 2006;49(5):1800-1807.

      [Crossref] [Google Scholar] [PubMed]

1081. Delaine T, Collins P, MacKinnon A, Sharma G, Stegmayr J, Rajput VK, et al. Galectin‐3‐binding glycomimetics that strongly reduce bleomycin‐induced lung fibrosis and modulate intracellular glycan recognition. Chembiochem. 2016;17(18):1759-1770.

      [Crossref] [Google Scholar] [PubMed]

1082. MacKinnon AC, Gibbons MA, Farnworth SL, Leffler H, Nilsson UJ, Delaine T, et al. Regulation of transforming growth factor-β1–driven lung fibrosis by galectin-3. Am J Respir Crit Care Med. 2012;185(5):537-546.

      [Crossref] [Google Scholar] [PubMed]

1083. Hsieh TJ, Lin HY, Tu Z, Lin TC, Wu SC, Tseng YY, et al. Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors. Sci Rep. 2016;6(1):29457.

      [Crossref] [Google Scholar] [PubMed]

1084. Zetterberg FR, Peterson K, Johnsson RE, Brimert T, Håkansson M, Logan DT, et al. Monosaccharide derivatives with low‐nanomolar lectin affinity and high selectivity based on combined Fluorine–Amide, Phenyl–Arginine, Sulfur–π, and halogen bond interactions. ChemMedChem. 2018;13(2):133-137.

      [Crossref] [Google Scholar] [PubMed]

1085. Zetterberg FR, MacKinnon A, Brimert T, Gravelle L, Johnsson RE, Kahl-Knutson B, et al. Discovery and optimization of the first highly effective and orally available galectin-3 inhibitors for treatment of fibrotic disease. J Med Chem. 2022;65(19):12626-12638.

      [Crossref] [Google Scholar] [PubMed]

1086. Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SE, Gregory CD, et al. An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade. Cancer Res. 2019;79(7):1480-1492.

      [Crossref] [Google Scholar] [PubMed]

1087. Zhang H, Liu P, Zhang Y, Han L, Hu Z, Cai Z, et al. Inhibition of galectin‐3 augments the antitumor efficacy of PD‐L1 blockade in non‐small‐cell lung cancer. FEBS Open Bio. 2021;11(3):911-920.

      [Crossref] [Google Scholar] [PubMed]

1088. Platt D, Raz A. Modulation of the lung colonization of B16-F1 melanoma cells by citrus pectin. JNCI: J Natl Cancer Inst. 1992;84(6):438-442.

      [Crossref] [Google Scholar] [PubMed]

1089. Pienta KJ, Nailk H, Akhtar A, Yamazaki K, Replogle TS, Lehr J, et al. Inhibition of spontaneous metastasis in a rat prostate cancer model by oral administration of modified citrus pectin. J Natl Cancer Inst. 1995;87(5):348-353.

      [Crossref] [Google Scholar] [PubMed]

1090. Demotte N, Wieërs G, Van Der Smissen P, Moser M, Schmidt C, Thielemans K, et al. A galectin-3 ligand corrects the impaired function of human CD4 and CD8 tumor-infiltrating lymphocytes and favors tumor rejection in mice. Cancer Res. 2010;70(19):7476-7488.

      [Crossref] [Google Scholar] [PubMed]

1091. Laderach DJ, Compagno D. Inhibition of galectins in cancer: Biological challenges for their clinical application. Front Immunol. 2023; 13:1104625.

      [Crossref] [Google Scholar] [PubMed]

1092. Kadoya T, Horie H. Structural and functional studies of galectin-1: A novel axonal regeneration-promoting activity for oxidized galectin-1. Curr Drug Targets. 2005;6(4):375-383.

      [Crossref] [Google Scholar] [PubMed]

1093. Teichberg VI, Silman I, Beitsch DD, Resheff G. A beta-D-galactoside binding protein from electric organ tissue of Electrophorus electricus. Proc Natl Acad Sci U S A. 1975;72(4):1383-1387.

      [Crossref] [Google Scholar] [PubMed]

1094. Yu X, Qian J, Ding L, Yin S, Zhou L, Zheng S. Galectin-1: A traditionally immunosuppressive protein displays context-dependent capacities. Int J Mol Sci. 2023;24(7):6501.

      [Crossref] [Google Scholar] [PubMed]

1095. You X, Liu Q, Wu J, Wang Y, Dai J, Chen D, et al. Galectin-1 promotes vasculogenic mimicry in gastric cancer by upregulating EMT signaling. J Cancer. 2019;10(25):6286. 

      [Crossref] [Google Scholar] [PubMed]

1096. Ito K, Stannard K, Gabutero E, Clark AM, Neo SY, Onturk S, et al. Galectin-1 as a potent target for cancer therapy: Role in the tumor microenvironment. Cancer Metastasis Rev. 2012; 31:763-778.

      [Crossref] [Google Scholar] [PubMed]

1097. Banh A, Zhang J, Cao H, Bouley DM, Kwok S, Kong C, et al. Tumor galectin-1 mediates tumor growth and metastasis through regulation of T-cell apoptosis. Cancer Res. 2011;71(13):4423-4431.

      [Crossref] [Google Scholar] [PubMed]

1098. Tang D, Yuan Z, Xue X, Lu Z, Zhang Y, Wang H, et al. High expression of Galectin‐1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int J Cancer. 2012;130(10):2337-2348.

      [Crossref] [Google Scholar] [PubMed]

1099. Perillo NL, Pace KE, Seilhamer JJ, Baum LG. Apoptosis of T cells mediated by galectin-1. Nature. 1995;378(6558):736-739.

      [Crossref] [Google Scholar] [PubMed]

1100. Koh HS, Lee C, Lee KS, Ham CS, Seong RH, Kim SS, et al. CD7 expression and galectin-1-induced apoptosis of immature thymocytes are directly regulated by NF-κB upon T-cell activation. Biochem Biophys Res Commun. 2008;370(1):149-153.

      [Crossref] [Google Scholar] [PubMed]

1101. Di Lella S, Sundblad V, Cerliani JP, Guardia CM, Estrin DA, Vasta GR, et al. When galectins recognize glycans: From biochemistry to physiology and back again. Biochemistry. 2011;50(37):7842-7857.

      [Crossref] [Google Scholar] [PubMed]

1102. Elola MT, Chiesa ME, Alberti AF, Mordoh J, Fink NE. Galectin-1 receptors in different cell types. J Biomed Sci. 2005; 12:13-29.

      [Crossref] [Google Scholar] [PubMed]

1103. Pace KE, Hahn HP, Pang M, Nguyen JT, Baum LG. Cutting edge: CD7 delivers a pro-apoptotic signal during galectin-1-induced T cell death. J Immunol. 2000;165(5):2331-2334.

      [Crossref] [Google Scholar] [PubMed]

1104. Thiemann S, Baum LG. Galectins and immune responses—just how do they do those things they do? Annu Rev Immunol. 2016;34(1):243-264.

      [Crossref] [Google Scholar] [PubMed]

1105. Xue J, Gao X, Fu C, Cong Z, Jiang H, Wang W, et al. Regulation of galectin-3-induced apoptosis of Jurkat cells by both O-glycans and N-glycans on CD45. FEBS Lett. 2013;587(24):3986-3994.

      [Crossref] [Google Scholar] [PubMed]

1106. Nguyen JT, Evans DP, Galvan M, Pace KE, Leitenberg D, Bui TN, et al. CD45 modulates galectin-1-induced T cell death: regulation by expression of core 2 O-glycans. J Immunol. 2001;167(10):5697-5707. 

      [Crossref] [Google Scholar] [PubMed]

1107. Cabrera PV, Amano M, Mitoma J, Chan J, Said J, Fukuda M, et al. Haploinsufficiency of C2GnT-I glycosyltransferase renders T lymphoma cells resistant to cell death. Blood. 2006;108(7):2399-2406.

      [Crossref] [Google Scholar] [PubMed]

1108. Merkle RK, Cummings RD. Asparagine-linked oligosaccharides containing poly-N-acetyllactosamine chains are preferentially bound by immobilized calf heart agglutinin. J Biol Chem. 1988;263(31):16143-16149.  

      [Crossref] [Google Scholar] [PubMed]

1109. Oda Y, Kasai KI. Photochemical cross-linking of β-galactoside-binding lectin to polylactosamino-proteoglycan of chick embryonic skin. Biochem Biophys Res Commun. 1984;123(3):1215-1220.

      [Crossref] [Google Scholar] [PubMed]

1110. Sparrow CP, Leffler H, Barondes SH. Multiple soluble beta-galactoside-binding lectins from human lung. J Biol Chem. 1987;262(15):7383-7390.

      [Google Scholar] [PubMed]

1111. Barondes SH, Cooper DN, Gitt MA, Leffler H. Galectins. Structure and function of a large family of animal lectins. J Biol Chem. 1994;269(33):20807-20810.

      [Google Scholar] [PubMed]

1112. Virgilio SD, Glushka J, Moremen K, Pierce M. Enzymatic synthesis of natural and 13C enriched linear poly-N-acetyllactosamines as ligands for galectin-1. Glycobiology. 1999;9(4):353-364.

      [Crossref] [Google Scholar] [PubMed]

1113. Rabinovich GA. Galectin-1 as a potential cancer target. Br J Cancer. 2005;92(7):1188-1192.

      [Crossref] [Google Scholar] [PubMed]

1114. Galvan M, Tsuboi S, Fukuda M, Baum LG. Expression of a specific glycosyltransferase enzyme regulates T cell death mediated by galectin-1. J Biol Chem. 2000;275(22):16730-16707.

      [Crossref] [Google Scholar] [PubMed]

1115. Baum LG, Derbin K, Perillo NL, Wu T, Pang M, Uittenbogaart C. Characterization of terminal sialic acid linkages on human thymocytes: correlation between lectin-binding phenotype and sialyltransferase expression. J Biol Chem. 1996;271(18):10793-10799. 

      [Crossref] [Google Scholar] [PubMed]

1116. Amano M, Galvan M, He J, Baum LG. The ST6Gal I Sialyltransferase selectively modifiesN-Glycans on CD45 to negatively regulate galectin-1-induced CD45 clustering, phosphatase modulation, and T cell death. J Biol Chem. 2003;278(9):7469-7475.

      [Crossref] [Google Scholar] [PubMed]

1117. Lantéri M, Giordanengo V, Hiraoka N, Fuzibet JG, Auberger P, Fukuda M, et al. Altered T cell surface glycosylation in HIV-1 infection results in increased susceptibility to galectin-1-induced cell death. Glycobiology. 2003;13(12):909-918.

      [Crossref] [Google Scholar] [PubMed]

1118. Earl LA, Bi S, Baum LG. N- and O-glycans modulate galectin-1 binding, CD45 signaling, and T cell death. J Biol Chem. 2010;285: 2232-2244.

      [Crossref] [Google Scholar] [PubMed]

1119. He J, Baum LG. Endothelial cell expression of galectin-1 induced by prostate cancer cells inhibits T-cell transendothelial migration. Lab Invest. 2006;86(6):578-590.

      [Crossref] [Google Scholar] [PubMed]

1120. Leffler H, SH Barondes. 1986. Specificity of binding of three soluble rat lung lectins to substituted and unsubstituted mammalian β-galactosides. J Biol Chem. 261: 10119-10126.

      [Crossref] [Google Scholar] [PubMed]

1121. Hernandez JD, Nguyen JT, He J, Wang W, Ardman B, Green JM, et al. Galectin-1 binds different CD43 glycoforms to cluster CD43 and regulate T cell death. J Immunol. 2006;177(8):5328-5336.

      [Crossref] [Google Scholar] [PubMed]

1122. Pace KE, Lee C, Stewart PL, Baum LG. Restricted receptor segregation into membrane microdomains occurs on human T cells during apoptosis induced by galectin-1. J Immunol. 1999;163:3801-3811.

      [Crossref] [Google Scholar] [PubMed]

1123. Hahn HP, Pang M, He J, Hernandez JD, Yang RY, Li LY, et al. Galectin-1 induces nuclear translocation of endonuclease G in caspase- and cytochrome c-independent T cell death. Cell Death Differ. 2004;11(12):1277-1286.

      [Crossref] [Google Scholar] [PubMed]

1124. Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, et al. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection; A potential mechanism of tumor-immune privilege. Cancer Cell. 2004;5(3):241-251.

      [Crossref] [Google Scholar] [PubMed]

1125. Nambiar DK, Aguilera T, Cao H, Kwok S, Kong C, Bloomstein J, et al. Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J Clin Invest. 2019;129(12):5553-5567.

      [Crossref] [Google Scholar] [PubMed]

1126. Rudjord-Levann AM, Ye Z, Hafkenscheid L, Horn S, Wiegertjes R, Nielsen MA, et al. Galectin-1 induces a tumor-associated macrophage phenotype and upregulates indoleamine 2,3-dioxygenase-1. iScience. 2023;26(7):106984.

      [Crossref] [Google Scholar] [PubMed]

1127. Juszczynski P, Ouyang J, Monti S, Rodig SJ, Takeyama K, Abramson J, et al. The AP1-dependent secretion of galectin-1 by reed Sternberg cells fosters immune privilege in classical Hodgkin lymphoma. Proc Natl Acad Sci USA. 2007;104(32):13134-13139.

      [Crossref] [Google Scholar] [PubMed]

1128. Juszczynski P, Rodig SJ, Ouyang J, O'Donnell E, Takeyama K, Mlynarski W, et al. MLL-rearranged B lymphoblastic leukemias selectively express the immunoregulatory carbohydrate-binding protein galectin-1. Clin Cancer Res. 2010;16(7):2122-2130. 

      [Crossref] [Google Scholar] [PubMed]

1129. Juszczynski P, Rodig SJ, Ouyang J, O'Donnell E, Takeyama K, Mlynarski W, et al. MLL-rearranged B lymphoblastic leukemias selectively express the immunoregulatory carbohydrate-binding protein galectin-1. Clin Cancer Res. 2010;16(7):2122-2130. 

      [Crossref] [Google Scholar] [PubMed]

1130. Li R, Colombo M, Wang G, Rodriguez-Romera A, Benlabiod C, Jooss NJ, et al. A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis. Sci Transl Med. 2024;16(768):eadj7552.

      [Crossref] [Google Scholar] [PubMed]

1131. Massaro M, Cagnoni AJ, Medrano FJ, Pérez-Sáez JM, Abdullayev S, Belkhadem K, et al. Selective modifications of lactose and N-acetyllactosamine with sulfate and aromatic bulky groups unveil unique structural insights in galectin-1-ligand recognition. Bioorg Med Chem. 2023;94:117480.

      [Crossref] [Google Scholar] [PubMed]

1132. Argüeso P, Panjwani N. Focus on molecules: Galectin-3. Exp Eye Res. 2011;92(1):2-3.

      [Crossref] [Google Scholar] [PubMed]

1133. Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al. Essentials of Glycobiology. Cold Spring Harbor Laboratory Press. 2022;491-504. 

      [Crossref] [Google Scholar] [PubMed]

1134. Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, et al. Essentials of Glycobiology. Cold Spring Harbor Laboratory Press. 2022;491-504. 

      [Crossref] [Google Scholar] [PubMed]

1135. Bumba L, Laaf D, Spiwok V, Elling L, Křen V, Bojarová P. Poly-N-Acetyllactosamine Neo-Glycoproteins as Nanomolar Ligands of Human Galectin-3: Binding Kinetics and Modeling. Int J Mol Sci. 2018;19:372.

      [Crossref] [Google Scholar] [PubMed]

1136. Haji-Ghassemi O, Gilbert M, Spence J, Schur MJ, Parker MJ, Jenkins ML, et al. Molecular basis for recognition of the cancer glycobiomarker, LacdiNAc (GalNAc [β1→ 4] GlcNAc), by Wisteria floribunda Agglutinin. J Biol Chem. 2016;291:24085-24095.

      [Crossref] [Google Scholar] [PubMed] 

1137. Nielsen MI, Stegmayr J, Grant OC, Yang Z, Nilsson UJ, Boos I, et al. Galectin binding to cells and glycoproteins with genetically modified glycosylation reveals galectin-glycan specificities in a natural context. J Biol Chem. 2018;293:20249-20262.

      [Crossref] [Google Scholar] [PubMed]

1138. Santos SN, Junqueira MS, Francisco G, Vilanova M, Magalhães A, Baruffi MD, et al. O-glycan sialylation alters galectin-3 subcellular localization and decreases chemotherapy sensitivity in gastric cancer. Oncotarget. 2016;7:83570. 

      [Crossref] [Google Scholar] [PubMed]

1139. Radziejewska I. Galectin-3 and Epithelial MUC1 Mucin-Interactions Supporting Cancer Development. Cancers (Basel). 2023;15(10):2680.

      [Crossref] [Google Scholar] [PubMed]

1140. Newlaczyl AU, Yu LG. Galectin-3--a jack-of-all-trades in cancer. Cancer Lett. 2011;313(2):123-128.

      [Crossref] [Google Scholar] [PubMed]

1141. Nieminen J, Kuno A, Hirabayashi J, Sato S. Visualization of galectin-3 oligomerization on the surface of neutrophils and endothelial cells using fluorescence resonance energy transfer. J Biol Chem. 2007;282(2):1374-1383.

      [Crossref] [Google Scholar] [PubMed]

1142. Nieminen J, Kuno A, Hirabayashi J, Sato S. Visualization of galectin-3 oligomerization on the surface of neutrophils and endothelial cells using fluorescence resonance energy transfer. J Biol Chem. 2007;282(2):1374-1383.

      [Crossref] [Google Scholar] [PubMed]

1143. Sato S, Nieminen J. Seeing strangers or announcing "danger": Galectin-3 in two models of innate immunity. Glycoconj J. 2002;19(7-9):583-591.

      [Crossref] [Google Scholar] [PubMed]

1144. Sato S. Galectins as molecules of danger signal, which could evoke an immune response to infection. Trends Glycosci Glyc. 2002;14:285-301.

      [Crossref] [Google Scholar]

1145. Lakshminarayan R, Wunder C, Becken U, Howes MT, Benzing C, Arumugam S, et al. Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat Cell Biol. 2014;16(6):595-606.

      [Crossref] [Google Scholar] [PubMed]

1146. Ewers H, Römer W, Smith AE, Bacia K, Dmitrieff S, Chai W, et al. GM1 structure determines SV40-induced membrane invagination and infection. Nat Cell Biol. 2010;12(1):11-12.

      [Crossref] [Google Scholar] [PubMed]

1147. Kabbani AM, Raghunathan K, Lencer WI, Kenworthy AK, Kelly CV. Structured clustering of the glycosphingolipid GM1 is required for membrane curvature induced by cholera toxin. Proc Natl Acad Sci. 2020;117(26):14978-14986.

      [Crossref] [Google Scholar] [PubMed]

1148. Römer W, Berland L, Chambon V, Gaus K, Windschiegl B, Tenza D, et al. Shiga toxin induces tubular membrane invaginations for its uptake into cells. Nature. 2007;450(7170):670-675.

      [Crossref] [Google Scholar]

1149. Ruvolo PP. Galectin 3 as a guardian of the tumor microenvironment. Biochim Biophys Acta. 2016;1863(3):427-437.

      [Crossref] [Google Scholar] [PubMed]

1150. Cardoso AC, Andrade LN, Bustos SO, Chammas R. Galectin-3 Determines Tumor Cell Adaptive Strategies in Stressed Tumor Microenvironments. Front Oncol. 2016;6:127.

      [Crossref] [Google Scholar] [PubMed]

1151. Perillo NL, Pace KE, Seilhamer JJ, Baum LG. Apoptosis of T cells mediated by galectin-1. Nature. 1995;378(6558):736-739.

      [Crossref] [Google Scholar] [PubMed]

1152. Fukumori T, Takenaka Y, Yoshii T, Kim HR, Hogan V, Inohara H, et al. CD29 and CD7 mediate galectin-3-induced type II T-cell apoptosis. Cancer Res. 2003;63(23):8302-8311.

      [Google Scholar] [PubMed]

1153. Stillman BN, Hsu DK, Pang M, Brewer CF, Johnson P, Liu FT, et al. Galectin-3 and galectin-1 bind distinct cell surface glycoprotein receptors to induce T cell death. J Immunol. 2006;176(2):778-789.

      [Crossref] [Google Scholar] [PubMed]

1154. Cousin JM, Cloninger MJ. The role of galectin-1 in cancer progression, and synthetic multivalent systems for the study of galectin-1. Int J Mol Sci. 2016;17(9):1566.

      [Crossref] [Google Scholar] [PubMed]

1155. Earl LA, Baum LG. CD45 glycosylation controls T-cell life and death. Immunol Cell Biol. 2008;86(7):608-615.

      [Crossref] [Google Scholar] [PubMed]

1156. Fortuna-Costa A, Gomes AM, Kozlowski EO, Stelling MP, Pavão MS. Extracellular galectin-3 in tumor progression and metastasis. Front Oncol. 2014;4:138.

      [Crossref] [Google Scholar] [PubMed]

1157. Demetriou M, Granovsky M, Quaggin S, Dennis JW. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature. 2001;409:733-739.

      [Crossref] [Google Scholar] [PubMed]

1158. Rabinovich GA, Croci DO. Regulatory circuits mediated by lectin-glycan interactions in autoimmunity and cancer. Immunity. 2012;36(3):322-335.

      [Crossref] [Google Scholar] [PubMed]

1159. Morgan R, Gao G, Pawling J, Dennis JW, Demetriou M, Li B. N-acetylglucosaminyltransferase V (Mgat5)-mediated N-glycosylation negatively regulates Th1 cytokine production by T cells. J Immunol. 2004;173(12):7200-7208.

      [Crossref] [Google Scholar] [PubMed]

1160. Grigorian A, Lee SU, Tian W, Chen IJ, Gao G, Mendelsohn R, et al. Control of T cell-mediated autoimmunity by metabolite flux to N-glycan biosynthesis. J Biol Chem 2007;282:20027–20035.

      [Crossref] [Google Scholar] [PubMed]

1161. Chen IJ, Chen HL, Demetriou M. Lateral compartmentalization of T cell receptor versus CD45 by galectin-N-glycan binding and microfilaments coordinate basal and activation signaling. J Biol Chem. 2007;282(48):35361-35372.

      [Crossref] [Google Scholar] [PubMed]

1162. Chen HY, Fermin A, Vardhana S, Weng IC, Lo KF, Chang EY, et al. Galectin-3 negatively regulates TCR-mediated CD4+ T-cell activation at the immunological synapse. Proc Natl Acad Sci U S A. 2009;106(34):14496-14501.

      [Crossref] [Google Scholar] [PubMed]

1163. Farhad M, Rolig AS, Redmond WL. The role of Galectin-3 in modulating tumor growth and immunosuppression within the tumor microenvironment. Oncoimmunology. 2018;7(6):e1434467.

      [Crossref] [Google Scholar] [PubMed]

1164. Ibrahim R, Saleh K, Chahine C, Khoury R, Khalife N, Cesne AL. LAG-3 inhibitors: Novel immune checkpoint inhibitors changing the landscape of immunotherapy. Biomedicines. 2023;11(7):1878.

      [Crossref] [Google Scholar] [PubMed]

1165. Lucas F, Pennell M, Huang Y, Benson DM, Efebera YA, Chaudhry M, et al. T cell transcriptional profiling and Immunophenotyping uncover LAG3 as a potential significant target of immune modulation in multiple myeloma. Biol Blood Marrow Transplant. 2020;26(1):7-15.

      [Crossref] [Google Scholar] [PubMed]

1166. Volkov DV, Stepanova VM, Rubtsov YP, Stepanov AV, Gabibov AG. Protein tyrosine phosphatase CD45 As an immunity regulator and a potential effector of CAR-T therapy. Acta Naturae. 2023;15(3):17-26.

      [Crossref] [Google Scholar] [PubMed]

1167. Clark MC, Pang M, Hsu DK, Liu FT, de Vos S, Gascoyne RD, et al. Galectin-3 binds to CD45 on diffuse large B-cell lymphoma cells to regulate susceptibility to cell death. Blood. 2012;120(23):4635-4644.

      [Crossref] [Google Scholar] [PubMed]

1168. Iurisci I, Tinari N, Natoli C, Angelucci D, Cianchetti E, Iacobelli S. Concentrations of galectin-3 in the sera of normal controls and cancer patients. Clin Cancer Res. 2000;6(4):1389-1393.

      [Google Scholar] [PubMed]

1169. Rodrigues JG, Balmaña M, Macedo JA, Poças J, Fernandes Â, de-Freitas-Junior JC, et al. Glycosylation in cancer: Selected roles in tumour progression, immune modulation and metastasis. Cell Immunol. 2018;333:46-57.

      [Crossref] [Google Scholar] [PubMed]

1170. Herbst RS, Fukuoka M, Baselga J. Gefitinib-a novel targeted approach to treating cancer. Nat Rev Cancer. 2004;4(12):956-965.

      [Crossref] [Google Scholar] [PubMed]

1171. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct Target Ther. 2020;5(1):28.

      [Crossref] [Google Scholar] [PubMed]

1172. Trendowski M. The inherent metastasis of leukaemia and its exploitation by sonodynamic therapy. Crit Rev Oncol Hematol. 2015;94(2):149-163.

      [Crossref] [Google Scholar] [PubMed]

1173. Ahmed H, AlSadek DM. Galectin-3 as a potential target to prevent cancer metastasis. Clin Med Insights Oncol. 2015;9:113-121.

      [Crossref] [Google Scholar] [PubMed]

1174. Ahmed H, Guha P, Kaptan E, Bandyopadhyaya G. Galectin-3: A potential target for cancer prevention. Trends Carbohydr Res. 2011;3(2):13-22. 

      [Crossref] [Google Scholar] [PubMed]

1175. Martin TA, Ye L, Sanders AJ, Lane J, Jiang WG. Cancer invasion and metastasis: Molecular and cellular perspective. Madame Curie Bioscience Database. 2013.

      [Google Scholar]

1176. Folkman J, Shing Y. Angiogenesis. J Biol Chem. 1992;267(16):10931-10934. 

      [Google Scholar] [PubMed]

1177. Folkman J. Fighting cancer by attacking its blood supply. Sci Am. 1996;275(3):150-154.

      [Crossref] [Google Scholar] [PubMed]

1178. Witz IP. The involvement of selectins and their ligands in tumor-progression. Immunol Lett. 2006;104(1-2):89-93.

      [Crossref] [Google Scholar] [PubMed]

1179. Krause T, Turner GA. Are selectins involved in metastasis? Clin Exp Metastasis. 1999;17(3):183-192.

      [Crossref] [Google Scholar] [PubMed]

1180. Burdick MM, McCaffery JM, Kim YS, Bochner BS, Konstantopoulos K. Colon carcinoma cell glycolipids, integrins, and other glycoproteins mediate adhesion to HUVECs under flow. Am J Physiol Cell Physiol 2003;284:C977-987. 

      [Crossref] [Google Scholar] [PubMed]

1181. Mannori G, Santoro D, Carter L, Corless C, Nelson RM, Bevilacqua MP. Inhibition of colon carcinoma cell lung colony formation by a soluble form of E-selectin. Am J Pathol 1997;151:233-243. 

      [Google Scholar] [PubMed]

1182. Fukuda MN, Ohyama C, Lowitz K, Matsuo O, Pasqualini R, Ruoslahti E, et al. A peptide mimic of E-selectin ligand inhibits sialyl Lewis X-dependent lung colonization of tumor cells. Cancer Res. 2000;60:450–456.

      [Google Scholar] [PubMed]

1183. Barthel SR, Wiese GK, Cho J, Opperman MJ, Hays DL, Siddiqui J, et al. Alpha 1,3 fucosyltransferases are master regulators of prostate cancer cell trafficking. Proc Natl Acad Sci USA 2009;106:19491-19496.

      [Crossref] [Google Scholar] [PubMed]

1184. Ruoslahti E. Integrins. J Clin Invest. 1991;87(1):1-5.

      [Crossref] [Google Scholar] [PubMed]

1185. Hynes RO. Integrins: Versatility, modulation, and signaling in cell adhesion. Cell. 1992;69(1):11-25.

      [Crossref] [Google Scholar] [PubMed]

1186. Qi J, Chen N, Wang J, Siu CH. Transendothelial migration of melanoma cells involves N-cadherin-mediated adhesion and activation of the beta-catenin signaling pathway. Mol Biol Cell. 2005;16(9):4386-4397.

      [Crossref] [Google Scholar] [PubMed]

1187. Sökeland G, Schumacher U. The functional role of integrins during intra- and extravasation within the metastatic cascade. Mol Cancer. 2019;18(1):12.

      [Crossref] [Google Scholar] [PubMed]

1188. Miles FL, Pruitt FL, van Golen KL, Cooper CR. Stepping out of the flow: Capillary extravasation in cancer metastasis. Clin Exp Metastasis. 2008;25(4):305-324.

      [Crossref] [Google Scholar] [PubMed]

1189. Strell C, Entschladen F. Extravasation of leukocytes in comparison to tumor cells. Cell Commun Signal. 2008;6:10.

      [Crossref] [Google Scholar] [PubMed]

1190. Nangia-Makker P, Sarvis R, Visscher DW, Bailey-Penrod J, Raz A, Sarkar FH. Galectin-3 and L1 retrotransposons in human breast carcinomas. Breast Cancer Res Treat. 1998;49(2):171-183.

      [Crossref] [Google Scholar] [PubMed]

1191. Koistinen P, Heino J. Integrins in cancer cell invasion. InMadame Curie Bioscience Database [Internet] Landes Bioscience. 2013.

      [Google Scholar]

1192. Borghi N, Lowndes M, Maruthamuthu V, Gardel ML, Nelson WJ. Regulation of Cell Motile Behavior by Crosstalk Between Cadherin- and Integrin-Mediated Adhesions. Proc Natl Acad Sci USA (2010) 107(30):13324–13329.

      [Crossref] [Google Scholar] [PubMed]

1193. Li Q, Lan T, Xie J, Lu Y, Zheng D, Su B. Integrin-mediated tumorigenesis and its therapeutic applications. Front Oncol. 2022;12:812480.

      [Crossref] [Google Scholar] [PubMed]

1194. Leask A. A centralized communication network: Recent insights into the role of the cancer associated fibroblast in the development of drug resistance in tumors. Semin Cell Dev Biol. 2020;101:111-114.

      [Crossref] [Google Scholar] [PubMed]

1195. Cooper J, Giancotti FG. Integrin Signaling in Cancer: Mechanotransduction, Stemness, Epithelial Plasticity, and Therapeutic Resistance. Cancer Cell. 2019;35(3):347-367.

      [Crossref] [Google Scholar] [PubMed]

1196. Bajaj J, Konuma T, Lytle NK, Kwon HY, Ablack JN, Cantor JM, et al. CD98-mediated adhesive signaling enables the establishment and propagation of acute myelogenous leukemia. Cancer Cell. 2016;30(5):792-805.

      [Crossref] [Google Scholar] [PubMed]

1197. Gu J, Taniguchi N. Regulation of integrin functions by N-glycans. Glycoconj J. 2004;21(1-2):9-15.

      [Crossref] [Google Scholar] [PubMed]

1198. Hou S, Hang Q, Isaji T, Lu J, Fukuda T, Gu J. Importance of membrane-proximal N-glycosylation on integrin β1 in its activation and complex formation. FASEB J. 2016;30(12):4120-4131.

      [Crossref] [Google Scholar] [PubMed]

1199. Pan D, Song Y. Role of altered sialylation of the I-like domain of beta1 integrin in the binding of fibronectin to beta1 integrin: Thermodynamics and conformational analyses. Biophys J. 2010;99(1):208-217.

      [Crossref] [Google Scholar] [PubMed]

1200. Li J, Su Y, Xia W, Qin Y, Humphries MJ, Vestweber D, et al. Conformational equilibria and intrinsic affinities define integrin activation. EMBO J. 2017;36(5):629-645.

      [Crossref] [Google Scholar]

1201. Hang Q, Isaji T, Hou S, Wang Y, Fukuda T, Gu J. A key regulator of cell adhesion: Identification and characterization of important N-glycosylation sites on integrin α 5 for cell migration. Mol Cell Biol. 2017 May 1;37(9):e00558.

      [Crossref] [Google Scholar] [PubMed]

1202. Shafaq-Zadah M, Dransart E, Wunder C, Chambon V, Valades-Cruz C, Leconte L, et al. Spatial N-glycan rearrangement on α 5 β 1 integrin nucleates galectin-3 oligomers to determine endocytic fate. bioRxiv. 2023.

      [Crossref] [Google Scholar] [PubMed]

1203. Shafaq-Zadah M, Gomes-Santos CS, Bardin S, Maiuri P, Maurin M, Iranzo J, et al. Persistent cell migration and adhesion rely on retrograde transport of β(1) integrin. Nat Cell Biol. 2016;18(1):54-64.

      [Crossref] [Google Scholar] [PubMed]

1204. Holst S, Wuhrer M, Rombouts Y. Glycosylation characteristics of colorectal cancer. Adv Cancer Res. 2015;126:203-256

      [Crossref] [Google Scholar] [PubMed]

1205. Boscher C, Nabi I. Galectin-3- and phospho-caveolin-1-dependent outside-in integrin signaling mediates the EGF motogenic response in mammary cancer cells. Mol Biol Cell. 2013;24(13):2134-2145. 

      [Crossref] [Google Scholar] [PubMed]

1206. Alge-Priglinger CS, André S, Schoeffl H, Kampik A, Strauss RW, Kernt M, et al. Negative regulation of RPE cell attachment by carbohydrate-dependent cell surface binding of galectin-3 and inhibition of the ERK-MAPK pathway. Biochimie. 2011;93(3):477-488

      [Crossref] [Google Scholar] [PubMed]

1207. Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, et al. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science. 2004;306(5693):120-124.

      [Crossref] [Google Scholar] [PubMed]

1208. Granovsky M, Fata J, Pawling J, Muller WJ, Khokha R, Dennis JW. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med. 2000;6(3):306-312.

      [Crossref] [Google Scholar] [PubMed]

1209. Demetriou M, Nabi IR, Coppolino M, Dedhar S, Dennis JW. Reduced contact-inhibition and substratum adhesion in epithelial cells expressing GlcNAc-transferase V. J Cell Biol. 1995;130(2):383-392.

      [Crossref] [Google Scholar] [PubMed]

1210. Kariya Y, Oyama M, Hashimoto Y, Gu J, Kariya Y. β4-Integrin/PI3K Signaling Promotes Tumor Progression through the Galectin-3-N-Glycan Complex. Mol Cancer Res. 2018;16(6):1024-1034.

      [Crossref] [Google Scholar] [PubMed]

1211. Zhao Y, Nakagawa T, Itoh S, Inamori KI, Isaji T, Kariya Y, et al. N-acetylglucosaminyltransferase III antagonizes the effect of N-acetylglucosaminyltransferase V on α3β1 integrin-mediated cell migration. J Biol Chem. 2006;281:32122–32130. 

      [Crossref] [Google Scholar] [PubMed]

1212. Lagana A, Goetz J, Cheung P, Raz A, Dennis J, Nabi I. Galectin binding to Mgat5-modified N-glycans regulates fibronectin matrix remodeling in tumor cells. Mol Cell Biol. 2006;26(8):3181-3193.

      [Crossref] [Google Scholar] [PubMed]

1213. Nangia-Makker P, Balan V, Raz A. Regulation of tumor progression by extracellular galectin-3. Cancer Microenviron. 2008;1(1):43-51.

      [Crossref] [Google Scholar] [PubMed]

1214. Hughes RC. Galectins as modulators of cell adhesion. Biochimie. 2001;83(7):667-676.

      [Crossref] [Google Scholar] [PubMed]

1215. Boscher C, Zheng Y, Lakshminarayan R, Johannes L, Dennis J, Foster L, et al. Galectin-3 protein regulates mobility of N-cadherin and GM1 ganglioside at cell-cell junctions of mammary carcinoma cells. J Biol Chem. 2012;287(39):32940-32952

      [Crossref] [Google Scholar] [PubMed]

1216. Loh CY, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, et al. the e-cadherin and n-cadherin switch in epithelial-to-mesenchymal transition: Signaling, therapeutic implications, and challenges. Cells. 2019;8(10):1118.

      [Crossref] [Google Scholar] [PubMed]

1217. Cao ZQ, Wang Z, Leng P. Aberrant N-cadherin expression in cancer. Biomed Pharmacother. 2019; 118:109320.

      [Crossref] [Google Scholar] [PubMed]

1218. Yu LG, Andrews N, Zhao Q, McKean D, Williams JF, Connor LJ, et al. Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. J Biol Chem. 2007;282(1):773-781.

      [Crossref] [Google Scholar] [PubMed]

1219. Glinsky VV, Glinsky GV, Rittenhouse-Olson K, Huflejt ME, Glinskii OV, Deutscher SL, et al. The role of Thomsen-Friedenreich antigen in adhesion of human breast and prostate cancer cells to the endothelium. Cancer Res. 2001;61(12):4851-4857. 

      [Google Scholar] [PubMed]

1220. Bian CF, Zhang Y, Sun H, Li DF, Wang DC. Structural basis for distinct binding properties of the human galectins to Thomsen-Friedenreich antigen. PLoS One. 2011;6(9): e25007.

      [Crossref] [Google Scholar] [PubMed]

1221. Ahmed H, Vasta GR, ANSELL B. Letter to the Glyco-Forum: Galections: Conservation of functionally and structurally relevant amino acid residues defines two types of carbohydrate recognition domains. Glycobiology. 1994;4(5):545-548.

      [Crossref] [Google Scholar] [PubMed]

1222. Bian CF, Zhang Y, Sun H, Li DF, Wang DC. Structural basis for distinct binding properties of the human galectins to Thomsen-Friedenreich antigen. PloS one. 2011;6(9): e25007. 

      [Crossref] [Google Scholar] [PubMed]

1223. Santarsia S, Grosso AS, Trovao F, Jiménez Barbero J, Carvalho AL, Nativi C, et al. Molecular recognition of a thomsen–friedenreich antigen mimetic targeting human galectin‐3. ChemMedChem. 2018;13(19):2030-2036.

      [Crossref] [Google Scholar] [PubMed]

1224. Yu LG, Andrews N, Zhao Q, McKean D, Williams JF, Connor LJ, et al. Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. J Biol Chem. 2007;282(1):773-781.

      [Crossref] [Google Scholar] [PubMed]

1225. Zhao Q, Guo X, Nash GB, Stone PC, Hilkens J, Rhodes JM, et al. Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res. 2009;69(17):6799-6806.

      [Crossref] [Google Scholar] [PubMed]

1226. Zhang K, Baeckström D, Brevinge H, Hansson GC. Secreted MUC1 mucins lacking their cytoplasmic part and carrying sialyl‐Lewis a and x epitopes from a tumor cell line and sera of colon carcinoma patients can inhibit HL‐60 leukocyte adhesion to E‐selectin‐expressing endothelial cells. J Cell Biochem. 1996;60(4):538-549.

      [Crossref] [Google Scholar] [PubMed]

1227. Zhao Q, Barclay M, Hilkens J, Guo X, Barrow H, Rhodes JM, et al. Interaction between circulating galectin-3 and cancer-associated MUC1 enhances tumour cell homotypic aggregation and prevents anoikis. Mol Cancer. 2010; 9:1-2. 

      [Crossref] [Google Scholar] [PubMed]

1228. Zhao Q, Guo X, Nash GB, Stone PC, Hilkens J, Rhodes JM, et al. Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res. 2009;69(17):6799-6806. 

      [Crossref] [Google Scholar] [PubMed]

1229. Cloosen S, Gratama J, Leeuwen EBV, Senden-Gijsbers BL, Oving EB, Mensdorff-Pouilly SV, et al. Cancer specific Mucin‐1 glycoforms are expressed on multiple myeloma. Br J Haematol. 2006;135(4):513-516.

      [Crossref] [Google Scholar] [PubMed]

1230. Piyush T, Chacko AR, Sindrewicz P, Hilkens J, Rhodes JM, Yu LG. Interaction of galectin-3 with MUC1 on cell surface promotes EGFR dimerization and activation in human epithelial cancer cells. Cell Death Differ. 2017;24(11):1937-1947. 

      [Crossref] [Google Scholar] [PubMed]

1231. Compagno D, Tiraboschi C, Garcia JD, Rondón Y, Corapi E, Velazquez C, et al. Galectins as checkpoints of the immune system in cancers, their clinical relevance, and implication in clinical trials. Biomolecules. 2020;10(5):750.

      [Crossref] [Google Scholar] [PubMed]

1232. Nath S, Mukherjee P. MUC1: A multifaceted oncoprotein with a key role in cancer progression. Trends Mol Med. 2014;20(6):332-342.  

      [Crossref] [Google Scholar] [PubMed]

1233. Merikhian P, Darvishi B, Jalili N, Esmailinejad MR, Khatibi AS, Kalbolandi SM, et al. Recombinant nanobody against MUC1 tandem repeats inhibits growth, invasion, metastasis, and vascularization of spontaneous mouse mammary tumors. Mol Oncol. 2022;16(2):485-507. 

      [Crossref] [Google Scholar] [PubMed]

1234. Zhao Q, Guo X, Nash GB, Stone PC, Hilkens J, Rhodes JM, et al. Circulating galectin-3 promotes metastasis by modifying MUC1 localization on cancer cell surface. Cancer Res. 2009;69(17):6799-6806.

      [Crossref] [Google Scholar] [PubMed]

1235. Nakahara S, Oka N, Raz A. On the role of galectin-3 in cancer apoptosis. Apoptosis. 2005; 10:267-275.

      [Crossref] [Google Scholar] [PubMed]

1236. Yang RY, Liu FT. Galectins in cell growth and apoptosis. Cell Mol Life Sci. 2003;60:267-276.

      [Crossref] [Google Scholar] [PubMed]

1237. Nangia Makker P, Nakahara S, Hogan V, Raz A. Galectin-3 in apoptosis, a novel therapeutic target. J Bioenerg Biomembr. 2007; 39:79-84.

      [Crossref] [Google Scholar] [PubMed]

1238. Kim HR, Lin HM, Biliran H, Raz A. Cell cycle arrest and inhibition of anoikis by galectin-3 in human breast epithelial cells. Cancer Res. 1999;59(16):4148-4154.  

      [Google Scholar] [PubMed]

1239. 1234. Fukumori T, Oka N, Takenaka Y, Nangia Makker P, Elsamman E, Kasai T, et al. Galectin-3 regulates mitochondrial stability and antiapoptotic function in response to anticancer drug in prostate cancer            . Cancer Res. 2006;66(6):3114-3119.

      [Crossref] [Google Scholar] [PubMed]

1240. Johnson KD, Glinskii OV, Mossine VV, Turk JR, Mawhinney TP, Anthony DC, et al. Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia. Neoplasia. 2007;9(8):662-670.

      [Crossref] [Google Scholar] [PubMed]

1241. Mirandola L, Yu Y, Chui K, Jenkins MR, Cobos E, John CM, et al. Galectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib in a murine model of human multiple myeloma. PLoS One. 2011;6(7): e21811.

      [Crossref] [Google Scholar] [PubMed]

1242. Dumic J, Dabelic S, Flögel M. Galectin-3: An open-ended story. Biochim Biophys Acta. 2006;1760(4):616-635.

      [Crossref] [Google Scholar] [PubMed]

1243. Balan V, Nangia Makker P, Schwartz AG, Jung YS, Tait L, Hogan V, et al. Racial disparity in breast cancer and functional germ line mutation in galectin-3 (rs4644): A pilot study. Cancer Res. 2008;68(24):10045-10050.

      [Crossref] [Google Scholar] [PubMed]

1244. Shimamura T, Sakamoto M, Ino Y, Shimada K, Kosuge T, Sato Y, et al. Clinicopathological significance of galectin-3 expression in ductal adenocarcinoma of the pancreas. Clin Cancer Res. 2002;8(8):2570-2575.  

      [Google Scholar] [PubMed]

1245. Collet JF, Hurbain I, Prengel C, Utzmann O, Scetbon F, Bernaudin JF, et al. Galectin-3 immunodetection in follicular thyroid neoplasms: A prospective study on fine-needle aspiration samples. Br J Cancer. 2005;93(10):1175-1181.

      [Crossref] [Google Scholar] [PubMed]

1246. Wang Y, Balan V, Gao X, Reddy PG, Kho D, Tait L, et al. The significance of galectin-3 as a new basal cell marker in prostate cancer. Cell Death Dis. 2013;4(8): e753.

      [Crossref] [Google Scholar] [PubMed]

1247. Sciacchitano S, Lavra L, Morgante A, Ulivieri A, Magi F, De Francesco GP, et al. Galectin-3: One molecule for an alphabet of diseases, from A to Z. Int J Mol Sci. 2018;19(2):379.

      [Crossref] [Google Scholar] [PubMed]

1248. Califice S, Castronovo V, Van Den Brûle F. Galectin-3 and cancer. Int J Onc. 2004;25(4):983-1075.  

      [Google Scholar] [PubMed]

1249. Fujita K, Iwama H, Oura K, Tadokoro T, Samukawa E, Sakamoto T, et al. Cancer therapy due to apoptosis: Galectin-9. Int J Mol Sci. 2017;18(1):74.

      [Crossref] [Google Scholar] [PubMed]

1250. Türeci Ö, Schmitt H, Fadle N, Pfreundschuh M, Sahin U. Molecular definition of a novel human galectin which is immunogenic in patients with Hodgkin's disease. J Biol Chem. 1997;272(10):6416-6422. 

      [Crossref] [Google Scholar] [PubMed]

1251. Wada J, Kanwar YS. Identification and characterization of galectin-9, a novel β-galactoside-binding mammalian lectin. J Biol Chem. 1997;272(9):6078-6086.

      [Crossref] [Google Scholar] [PubMed]

1252. Moure MJ, Gimeno A, Delgado S, Diercks T, Boons GJ, Jiménez Barbero J, et al. selective 13c‐labels on repeating glycan oligomers to reveal protein binding epitopes through NMR: Polylactosamine binding to galectins. Angew Chem Int Ed Engl. 2021;60(34):18777-18782.

      [Crossref] [Google Scholar] [PubMed]

1253. Giovannone N, Liang J, Antonopoulos A, Geddes Sweeney J, King SL, Pochebit SM, et al. Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans. Nat Commun. 2018;9(1):3287. 

      [Crossref] [Google Scholar] [PubMed]

1254. Moar P, Tandon R. Galectin-9 as a biomarker of disease severity. Cell Immunol. 2021; 361:104287.

      [Crossref] [Google Scholar] [PubMed]

1255. Earl LA, Bi S, Baum LG. Galectin multimerization and lattice formation are regulated by linker region structure. Glycobiology. 2011;21(1):6-12.

      [Crossref] [Google Scholar] [PubMed] 

1256. Chou FC, Chen HY, Kuo CC, Sytwu HK. Role of galectins in tumors and in clinical immunotherapy. Int J Mol Sci. 2018;19(2):430.

      [Crossref] [Google Scholar] [PubMed]

1257. Kruk L, Braun A, Cosset E, Gudermann T, Mammadova Bach E. Galectin functions in cancer-associated inflammation and thrombosis. Front Cardiovasc Med. 2023; 10:1052959.

      [Crossref] [Google Scholar] [PubMed]

1258. Rodrigues CF, Santos FA, Amorim LA, da Silva AL, Marques LG, Rocha BA. Galectin-9 is a target for the treatment of cancer: A patent review. Int J Biol Macromol. 2024; 254:127768.

      [Crossref] [Google Scholar] [PubMed]

1259. Lv Y, Ma X, Ma Y, Du Y, Feng J. A new emerging target in cancer immunotherapy: Galectin-9 (LGALS9). Genes Dis. 2023;10(6):2366-2382.

      [Crossref] [Google Scholar] [PubMed]

1260. Liang T, Wang X, Wang F, Feng E, You G. Galectin-9: A predictive biomarker negatively regulating immune response in glioma patients. World Neurosurg. 2019;132: e455-462.

      [Crossref] [Google Scholar] [PubMed]

1261. Seifert AM, Reiche C, Heiduk M, Tannert A, Meinecke AC, Baier S, et al. Detection of pancreatic ductal adenocarcinoma with galectin-9 serum levels. Oncogene. 2020;39(15):3102-3113.

      [Crossref] [Google Scholar] [PubMed]

1262. Sideras K, Biermann K, Yap K, Mancham S, Boor PP, Hansen BE, et al. Tumor cell expression of immune inhibitory molecules and tumor‐infiltrating lymphocyte count predict cancer‐specific survival in pancreatic and ampullary cancer. Int J Cancer. 2017;141(3):572-582.

      [Crossref] [Google Scholar] [PubMed]

1263. Zhang Y, Xue S, Hao Q, Liu F, Huang W, Wang J. Galectin-9 and PSMB8 overexpression predict unfavorable prognosis in patients with AML. J Cancer. 2021;12(14):4257.

      [Crossref] [Google Scholar] [PubMed]

1264. Yang R, Sun L, Li CF, Wang YH, Xia W, Liu B, et al. Development and characterization of anti-galectin-9 antibodies that protect T cells from galectin-9-induced cell death. J Biol Chem. 2022;298(4).

      [Crossref] [Google Scholar] [PubMed]

1265. Fujita K, Iwama H, Sakamoto T, Okura R, Kobayashi K, Takano J, et al. Galectin-9 suppresses the growth of hepatocellular carcinoma via apoptosis in vitro and in vivo. Int J Oncol. 2015;46(6):2419-2430.

      [Crossref] [Google Scholar] [PubMed]

1266. Zhang ZY, Dong JH, Chen YW, Wang XQ, Li CH, Wang J, et al. Galectin-9 acts as a prognostic factor with antimetastatic potential in hepatocellular carcinoma. Asian Pac J Cancer Prev. 2012;13(6):2503-2509.

      [Crossref] [Google Scholar] [PubMed]

1267. Nobumoto A, Nagahara K, Oomizu S, Katoh S, Nishi N, Takeshita K, et al. Galectin-9 suppresses tumor metastasis by blocking adhesion to endothelium and extracellular matrices. Glycobiology. 2008;18(9):735-744.

      [Crossref] [Google Scholar] [PubMed]

1268. Fujihara S, Mori H, Kobara H, Rafiq K, Niki T, Hirashima M, et ak. Galectin-9 in cancer therapy. Recent Pat Endocr Metab Immune Drug Discov. 2013;7(2):130-137.

      [Crossref] [Google Scholar] [PubMed]

1269. Bi S, Hong PW, Lee B, Baum LG. Galectin-9 binding to cell surface protein disulfide isomerase regulates the redox environment to enhance T-cell migration and HIV entry. Proc Natl Acad Sci U S A. 2011;108(26):10650-10655.

      [Crossref] [Google Scholar] [PubMed]

1270. Katoh S, Ishii N, Nobumoto A, Takeshita K, Dai SY, Shinonaga R, et al. Galectin-9 inhibits CD44–hyaluronan interaction and suppresses a murine model of allergic asthma. Am J Respir Crit Care Med. 2007;176(1):27-35.

      [Crossref] [Google Scholar] [PubMed]

1271. Iqbal AJ, Krautter F, Blacksell IA, Wright RD, Austin Williams SN, Voisin MB, et al. Galectin‐9 mediates neutrophil capture and adhesion in a CD44 and β2 integrin‐dependent manner. The FASEB Journal. 2022;36(1): e22065.

      [Crossref] [Google Scholar] [PubMed]

1272. Bi S, Earl LA, Jacobs L, Baum LG. Structural features of galectin-9 and galectin-1 that determine distinct T cell death pathways. J Biol Chem. 2008;283(18):12248-12258.

      [Crossref] [Google Scholar] [PubMed]

1273. Lau LS, Mohammed NB, Dimitroff CJ. Decoding strategies to evade Immunoregulators Galectin-1,-3, and-9 and their ligands as novel Therapeutics in cancer Immunotherapy. Int J Mol Sci. 2022;23(24):15554.

      [Crossref] [Google Scholar] [PubMed]

1274. Kikushige Y, Miyamoto T, Yuda J, Jabbarzadeh Tabrizi S, Shima T, Takayanagi SI, et al. A TIM-3/Gal-9 autocrine stimulatory loop drives self-renewal of human myeloid leukemia stem cells and leukemic progression. Cell Stem Cell. 2015;17(3):341-352.

      [Crossref] [Google Scholar] [PubMed]

1275. Silva IG, Yasinska IM, Sakhnevych SS, Fiedler W, Wellbrock J, Bardelli M, et al. The Tim-3-galectin-9 secretory pathway is involved in the immune escape of human acute myeloid leukemia cells. EBioMedicine. 2017; 22:44-57.

      [Crossref] [Google Scholar] [PubMed]

1276. Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20(3):173-185.

      [Crossref] [Google Scholar] [PubMed]

1277. Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood. 2011;117(17):4501-4510.

      [Crossref] [Google Scholar] [PubMed]

1278. Golden Mason L, McMahan RH, Strong M, Reisdorph R, Mahaffey S, Palmer BE, et al. Galectin-9 functionally impairs natural killer cells in humans and mice. J Virol. 2013;87(9):4835-4845.

      [Crossref] [Google Scholar] [PubMed]

1279. Ndhlovu LC, Lopez Vergès S, Barbour JD, Jones RB, Jha AR, Long BR, et al. Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity. Blood. 2012;119(16):3734-3743.

      [Crossref] [Google Scholar] [PubMed]

1280. Silva IG, Rüegg L, Gibbs BF, Bardelli M, Fruehwirth A, Varani L, et al. The immune receptor Tim-3 acts as a trafficker in a Tim-3/galectin-9 autocrine loop in human myeloid leukemia cells. Oncoimmunology. 2016;5(7): e1195535.

      [Crossref] [Google Scholar] [PubMed]

1281. Kikushige Y, Miyamoto T. TIM-3 as a novel therapeutic target for eradicating acute myelogenous leukemia stem cells. Int J Hematol. 2013; 98:627-633.

      [Crossref] [Google Scholar] [PubMed]

1282. Golden Mason L, McMahan RH, Strong M, Reisdorph R, Mahaffey S, Palmer BE, et al. Galectin-9 functionally impairs natural killer cells in humans and mice. Journal of virology. 2013;87(9):4835-4845.

      [Crossref] [Google Scholar] [PubMed]

1283. Wang F, He W, Zhou H, Yuan J, Wu K, Xu L, et al. The Tim-3 ligand galectin-9 negatively regulates CD8+ alloreactive T cell and prolongs survival of skin graft. Cell Immunol. 2007;250(1-2):68-74.

      [Crossref] [Google Scholar] [PubMed]

1284. Choukrani G, Visser N, Ustyanovska Avtenyuk N, Olthuis M, Marsman G, Ammatuna E, et al. Galectin-9 has non-apoptotic cytotoxic activity toward acute myeloid leukemia independent of cytarabine resistance. Cell Death Discov. 2023;9(1):228.

      [Crossref] [Google Scholar] [PubMed]

1285. Okudaira T, Hirashima M, Ishikawa C, Makishi S, Tomita M, Matsuda T, et al. A modified version of galectin-9 suppresses cell growth and induces apoptosis of human T-cell leukemia virus type I-infected T-cell lines Int J Cancer. 2011;129(11):2762.

      [Crossref] [Google Scholar] [PubMed]

1286. Kashio Y, Nakamura K, Abedin MJ, Seki M, Nishi N, Yoshida N, et al. Galectin-9 induces apoptosis through the calcium-calpain-caspase-1 pathway. J Immunol. 2003;170(7):3631-3636.

      [Crossref] [Google Scholar] [PubMed]

1287. Kobayashi T, Kuroda J, Ashihara E, Oomizu S, Terui Y, Taniyama A, et al. Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways. Leukemia. 2010;24(4):843-850.

      [Crossref] [Google Scholar] [PubMed]

1288. Kuroda J, Yamamoto M, Nagoshi H, Kobayashi T, Sasaki N, Shimura Y, et al. Targeting activating transcription factor 3 by Galectin-9 induces apoptosis and overcomes various types of treatment resistance in chronic myelogenous leukemia. Mol Cancer Res. 2010;8(7):994-1001.

      [Crossref] [Google Scholar] [PubMed]

1289. Makishi S, Okudaira T, Ishikawa C, Sawada S, Watanabe T, Hirashima M, et al. Retracted: A modified version of galectin‐9 induces cell cycle arrest and apoptosis of Burkitt and Hodgkin lymphoma cells. Br J Haematol. 2008;142(4):583-594.

      [Crossref] [Google Scholar] [PubMed]

1290. Kobayashi T, Kuroda J, Ashihara E, Oomizu S, Terui Y, Taniyama A, et al. Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways. Leukemia. 2010;24(4):843-850.

      [Crossref] [Google Scholar] [PubMed]

1291. Wiersma VR, de Bruyn M, Helfrich W, Bremer E. Therapeutic potential of Galectin‐9 in human disease. Med Res Rev. 2013;33(S1): E102-E126.

      [Crossref] [Google Scholar] [PubMed]

1292. Yin J, Li L, Wang C, Zhang Y. Increased Galectin-9 expression, a prognostic biomarker of aGVHD, regulates the immune response through the Galectin-9 induced MDSC pathway after allogeneic hematopoietic stem cell transplantation. Int Immunopharmacol. 2020; 88:106929.

      [Crossref] [Google Scholar] [PubMed]

1293. Wang Z, Chen J, Wang M, Zhang L, Yu L. One stone, two birds: The roles of Tim-3 in acute myeloid leukemia. Front Immunol. 2021; 12:618710.

      [Crossref] [Google Scholar] [PubMed]

1294. Sabatos Peyton C, Longmire T, Baker L, Patel N, Wavreille AS, Verneret M, et al. 439 Dual modes of action for anti-TIM-3 antibody MBG453 in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML): Preclinical evidence for immune-mediated and anti-leukemic activity.

      [Google Scholar]

1295. Zeidan AM, Esteve J, Giagounidis A, Kim HJ, Miyazaki Y, Platzbecker U, et al. The STIMULUS program: Clinical trials evaluating sabatolimab (MBG453) combination therapy in patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS) or Acute Myeloid Leukemia (AML). Blood. 2020;136:45-46.

      [Crossref] [Google Scholar]

1296. Demir D. Insights into the new molecular updates in acute myeloid leukemia pathogenesis. Genes. 2023;14(7):1424.

      [Crossref] [Google Scholar] [PubMed]

1297. Brunner AM, Esteve J, Porkka K, Knapper S, Vey N, Scholl S, et al. Efficacy and safety of sabatolimab (MBG453) in combination with Hypomethylating Agents (HMAs) in patients with Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndrome (HR-MDS): Updated results from a phase 1b study. Blood. 2020; 136:1-2.

      [Crossref] [Google Scholar]

1298. Zeidan AM, Westermann J, Kovacsovics T, Assouline S, Schuh AC, Kim HJ, et al. P582: First results of a phase ii study (stimulus-aml1) investigating sabatolimab+ azacitidine+ venetoclax in patients with newly diagnosed acute myeloid leukemia. HemaSphere. 2022; 6:481-2.  

      [Crossref] [Google Scholar]

1299. Jandus C, Boligan KF, Chijioke O, Liu H, Dahlhaus M, Démoulins T, et al. Interactions between Siglec-7/9 receptors and ligands influence NK cell–dependent tumor immunosurveillance. J Clin Invest. 2014;124(4):1810-1820.

      [Crossref] [Google Scholar] [PubMed]

1300. Stanczak MA, Läubli H. Siglec receptors as new immune checkpoints in cancer. Mol Aspects Med. 2023; 90:101112.

      [Crossref] [Google Scholar] [PubMed]

1301. Bartish M, Del Rincón SV, Rudd CE, Saragovi HU. Aiming for the sweet spot: Glyco-immune checkpoints and γδ T cells in targeted immunotherapy. Front Immunol. 2020; 11:564499.

      [Crossref] [Google Scholar] [PubMed]

1302. Bärenwaldt A, Läubli H. The sialoglycan-Siglec glyco-immune checkpoint–a target for improving innate and adaptive anti-cancer immunity. Expert Opin Ther Targets. 2019;23(10):839-853.

      [Crossref] [Google Scholar] [PubMed]

1303. Pedram K, Shon DJ, Tender GS, Mantuano NR, Northey JJ, Metcalf KJ, et al. Design of a mucin-selective protease for targeted degradation of cancer-associated mucins. Nat Biotechnol. 2024;42(4):597-607.

      [Crossref] [Google Scholar] [PubMed]

1304. Fraschilla I, Pillai S. Viewing Siglecs through the lens of tumor immunology. Immunol Rev. 2017;276(1):178-191.

      [Crossref] [Google Scholar] [PubMed]

1305. Raulet DH, Vance RE. Self-tolerance of natural killer cells. Nat Rev Immunol. 2006;6(7):520-531.

      [Crossref] [Google Scholar] [PubMed]

1306. Buri MC, Shoeb MR, Bykov A, Repiscak P, Baik H, Dupanovic A, et al. Natural killer cell cytotoxicity shapes the clonal evolution of B cell leukaemia. bioRxiv. 2023:2023-11.

      [Crossref] [Google Scholar]

1307. Jandus C, Boligan KF, Chijioke O, Liu H, Dahlhaus M, Démoulins T, et al. Interactions between Siglec-7/9 receptors and ligands influence NK cell–dependent tumor immunosurveillance. J Clin Invest. 2014;124(4):1810-1820.

      [Crossref] [Google Scholar] [PubMed]

1308. Hudak JE, Canham SM, Bertozzi CR. Glycocalyx engineering reveals a Siglec-based mechanism for NK cell immunoevasion. Nat Chem Biol. 2014;10(1):69-75.

      [Crossref] [Google Scholar] [PubMed]

1309. Rodriguez E, Boelaars K, Brown K, Eveline Li RJ, Kruijssen L, Bruijns SC, et al. Sialic acids in pancreatic cancer cells drive tumour-associated macrophage differentiation via the Siglec receptors Siglec-7 and Siglec-9. Nat Commun. 2021;12(1):1270.

      [Crossref] [Google Scholar] [PubMed]

1310. Beatson R, Tajadura Ortega V, Achkova D, Picco G, Tsourouktsoglou TD, Klausing S, et al. The mucin MUC1 modulates the tumor immunological microenvironment through engagement of the lectin Siglec-9. Nat Immunol. 2016;17(11):1273-1281.

      [Crossref] [Google Scholar] [PubMed]

1311. Beatson R, Graham R, Grundland Freile F, Cozzetto D, Kannambath S, Pfeifer E, et al. Cancer-associated hypersialylated MUC1 drives the differentiation of human monocytes into macrophages with a pathogenic phenotype. Commun Biol. 2020;3(1):644.

      [Crossref] [Google Scholar] [PubMed]

1312. Friedman DJ, Crotts SB, Shapiro MJ, Rajcula M, McCue S, Liu X, et al. ST8Sia6 promotes tumor growth in mice by inhibiting immune responses. Cancer Immunol Res. 2021;9(8):952-966.

      [Crossref] [Google Scholar] [PubMed]

1313. Friedman DJ, Kizerwetter M, Belmonte P, Rajcula M, Theodore K, Kim Lee HS, et al. Cutting edge: Enhanced antitumor immunity in ST8Sia6 knockout mice. J Immunol. 2022;208(8):1845-1850.

      [Crossref] [Google Scholar] [PubMed]

1314. Ibarlucea Benitez I, Weitzenfeld P, Smith P, Ravetch JV. Siglecs-7/9 function as inhibitory immune checkpoints in vivo and can be targeted to enhance therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2021;118(26): e2107424118.

      [Crossref] [Google Scholar] [PubMed]

1315. Jandus C, Boligan KF, Chijioke O, Liu H, Dahlhaus M, Démoulins T, Schneider C, Wehrli M, Hunger RE, Baerlocher GM, Simon HU. Interactions between Siglec-7/9 receptors and ligands influence NK cell–dependent tumor immunosurveillance. J Clin Invest. 2014;124(4):1810-1820.

      [Crossref] [Google Scholar] [PubMed]

1316. O’Dwyer M, Glavey S, McAvera R, Natoni A, Ryan AE. Hypersialylation and multiple myeloma. Front.Hematol. 2024; 3:1360149.

      [Google Scholar]

1317. Daly J, Sarkar S, Natoni A, Stark JC, Riley NM, Bertozzi CR, et al. Targeting hypersialylation in multiple myeloma represents a novel approach to enhance NK cell–mediated tumor responses. Blood Adv.2022;6(11):3352-3366.

      [Crossref] [Google Scholar] [PubMed]

1318. Azab AK, Quang P, Azab F, Pitsillides C, Thompson B, Chonghaile T, et al. P-selectin glycoprotein ligand regulates the interaction of multiple myeloma cells with the bone marrow microenvironment. Blood. 2012;119(6):1468-1478.

      [Crossref] [Google Scholar] [PubMed]

1319. Zerdan MB, Nasr L, Kassab J, Saba L, Ghossein M, Yaghi M, et al. Adhesion molecules in multiple myeloma oncogenesis and targeted therapy. Int J Hematol Oncol. 2022;11(2): IJH39.

      [Crossref] [Google Scholar] [PubMed]

1320. Yoshimura A, Asahina Y, Chang LY, Angata T, Tanaka H, Kitajima K, et al. Identification and functional characterization of a Siglec-7 counter-receptor on K562 cells. J Biol Chem. 2021;296.

      [Crossref] [Google Scholar] [PubMed]

1321. Wisnovsky S, Möckl L, Malaker SA, Pedram K, Hess GT, Riley NM, et al. Genome-wide CRISPR screens reveal a specific ligand for the glycan-binding immune checkpoint receptor Siglec-7. Proc Natl Acad Sci U S A. 2021;118(5): e2015024118.

      [Crossref] [Google Scholar] [PubMed]

1322. Stewart N, Daly J, Drummond Guy O, Krishnamoorthy V, Stark JC, Riley NM, et al. The glycoimmune checkpoint receptor Siglec-7 interacts with T-cell ligands and regulates T-cell activation. J Biol Chem. 2024;300(2).

      [Crossref] [Google Scholar] [PubMed]

1323. Stewart N, Daly J, Drummond Guy O, Krishnamoorthy V, Stark JC, Riley NM, et al. The glycoimmune checkpoint receptor Siglec-7 interacts with T-cell ligands and regulates T-cell activation. J Biol Chem. 2024;300(2).

      [Crossref] [Google Scholar] [PubMed]

1324. Zhuang X, Woods J, Ji Y, Scheich S, Mo F, Rajagopalan S, et al. Functional genomics identifies N-acetyllactosamine extension of complex N-glycans as a mechanism to evade lysis by natural killer cells. Cell Rep. 2024;43(4).

      [Crossref] [Google Scholar] [PubMed]

1325. Kadirvelraj R, Yang JY, Kim HW, Sanders JH, Moremen KW, Wood ZA. Comparison of human poly-N-acetyl-lactosamine synthase structure with GT-A fold glycosyltransferases supports a modular assembly of catalytic subsites. J Biol Chem. 202;296.

      [Crossref] [Google Scholar] [PubMed]

1326. Dersh D, Phelan JD, Gumina ME, Wang B, Arbuckle JH, Holly J, et al. Genome-wide screens identify lineage-and tumor-specific genes modulating MHC-I-and MHC-II-restricted immunosurveillance of human lymphomas. Immunity. 2021;54(1):116-131.

      [Crossref] [Google Scholar] [PubMed]

1327. Dufva O, Gandolfi S, Huuhtanen J, Dashevsky O, Duàn H, Saeed K, et al. Single-cell functional genomics reveals determinants of sensitivity and resistance to natural killer cells in blood cancers. Immunity. 2023;56(12):2816-2835.

      [Crossref] [Google Scholar] [PubMed]

1328. Manni M, Läubli H. Targeting glyco-immune checkpoints for cancer therapy. Expert Opin Biol Ther. 2021;21(8):1063-1071.

      [Crossref] [Google Scholar] [PubMed]

1329. Ereño Orbea J, Sicard T, Cui H, Mazhab Jafari MT, Benlekbir S, Guarné A, et al. Molecular basis of human CD22 function and therapeutic targeting. Nat Commun. 2017;8(1):764.

      [Crossref] [Google Scholar] [PubMed]

1330. Vaickus L, Ball ED, Foon KA. Immune markers in hematologic malignancies. Crit Rev Oncol Hematol. 1991;11(4):267-297.

      [Crossref] [Google Scholar] [PubMed]

1331. Schwartz Albiez R, Dörken B, Monner DA, Moldenhauer G. CD22 antigen: Biosynthesis, glycosyiation and surface expression of a B lymphocyte protein involved in B cell activation and adhesion. Int Immunol. 1991;3(7):623-633.

      [Crossref] [Google Scholar] [PubMed]

1332. Jabbour E, O Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010-4016.

      [Crossref] [Google Scholar] [PubMed]

1333. Rousselot P. Old rivals become new friends. Blood. 2024;143(5):380-382.

      [Crossref] [Google Scholar] [PubMed]

1334. Rubinstein JD, O’Brien MM. Inotuzumab ozogamicin in B-cell precursor acute lymphoblastic leukemia: efficacy, toxicity, and practical considerations. Front Immunol. 2023;14:1237738. 

      [Crossref] [Google Scholar] [PubMed]

1335. Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753.

      [Crossref] [Google Scholar] [PubMed]

1336. DeAngelo DJ, Advani AS, Marks DI, Stelljes M, Liedtke M, Stock W, et al. Inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: Outcomes by disease burden. Blood Cancer J. 2020;10(8):81.

      [Crossref] [Google Scholar] [PubMed]

1337. Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: A multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57-66.

      [Crossref] [Google Scholar] [PubMed]

1338. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378(5):449-459.

      [Crossref] [Google Scholar] [PubMed]

1339. Short NJ, Jabbour E, Jain N, Kantarjian H. Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: Past progress, current research and future directions. J Hematol Oncol. 2024;17(1):32.

      [Crossref] [Google Scholar] [PubMed]

1340. Jabbour E, Haddad FG, Short NJ, Senapati J, Jain N, Sasaki K, et al. Phase 2 study of inotuzumab ozogamicin for measurable residual disease in acute lymphoblastic leukemia in remission. Blood. 2024;143(5):417-421.

      [Crossref] [Google Scholar] [PubMed]

1341. Spiegel JY, Patel S, Muffly L, Hossain NM, Oak J, Baird JH, et al. CAR T cells with dual targeting of CD19 and CD22 in adult patients with recurrent or refractory B cell malignancies: A phase 1 trial. Nat Med. 2021;27(8):1419-1431.

      [Crossref] [Google Scholar] [PubMed]

1342. Meckler JF, Levis DJ, Vang DP, Tuscano JM. A Novel bispecific T-cell engager (BiTE) targeting CD22 and CD3 has both in vitro and in vivo activity and synergizes with blinatumomab in an acute lymphoblastic leukemia (ALL) tumor model. Cancer Immunol Immunother. 2023;72(9):2939-2948.

      [Crossref] [Google Scholar] [PubMed]

1343. Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study. Lancet 2012;379(9825):1508-1516.

      [Crossref] [Google Scholar] [PubMed]

1344. Walter RB. Expanding use of CD33-directed immunotherapy. Expert Opin Biolog Ther. 2020;20(9):955-958.

      [Crossref] [Google Scholar] [PubMed]

1345. Baron J, Wang ES. Gemtuzumab ozogamicin for the treatment of acute myeloid leukemia. Expert Rev Clin Pharmacol. 2018;11(6):549-559.

      [Crossref] [Google Scholar] [PubMed]

1346. Hills RK, Castaigne S, Appelbaum FR, Delaunay J, Petersdorf S, Othus M, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: A meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986-996.

      [Crossref] [Google Scholar] [PubMed]

1347. Fatobene G, Souza GR, Rodrigues CA, Novis YA, Rocha V. Gemtuzumab ozogamicin is efficacious in attaining complete remission in relapsed/refractory acute leukemia prior to hematopoietic cell transplant: A case series. Hematol Transfus Cell Ther. 2021;43(04):532-536.

      [Crossref] [Google Scholar] [PubMed]

1348. Yilmaz M, Richard S, Jabbour E. The clinical potential of inotuzumab ozogamicin in relapsed and refractory acute lymphocytic leukemia. Ther Adv Hematol. 2015;6(5):253-261.

      [Crossref] [Google Scholar] [PubMed]

1349. Linenberger ML, Hong T, Flowers D, Sievers EL, Gooley TA, Bennett JM, et al. Multidrug-resistance phenotype and clinical responses to gemtuzumab ozogamicin. Blood. 2001;98(4):988-994.

      [Crossref] [Google Scholar] [PubMed]

1350. Walter RB, Gooley TA, Van Der Velden VH, Loken MR, Van Dongen JJ, Flowers DA, et al. CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy. Blood. 2007;109(10):4168-4170.

      [Crossref] [Google Scholar] [PubMed]

1351. Meany DL, Chan DW. Aberrant glycosylation associated with enzymes as cancer biomarkers. Clin Proteomics. 2011;8:1-4.

      [Crossref] [Google Scholar] [PubMed]

1352. Munkley J. Aberrant sialylation in cancer: Therapeutic opportunities. Cancers. 2022;14(17):4248.

      [Crossref] [Google Scholar] [PubMed]

1353. Orozco-Moreno M, Visser EA, Hodgson K, Hipgrave Ederveen AL, Bastian K, Goode EA, et al. Targeting aberrant sialylation and fucosylation in prostate cancer cells using potent metabolic inhibitors. Glycobiology. 2023;33(12):1155-1171.

      [Crossref] [Google Scholar] [PubMed]

1354. Ayyalasomayajula R, Cudic M. Targeting siglec-sialylated MUC1 immune axis in cancer. Cancers. 2024;16(7):1334.

      [Crossref] [Google Scholar] [PubMed]

1355. Parameswaran R, Lim M, Arutyunyan A, Abdel-Azim H, Hurtz C, Lau K, et al. O-acetylated N-acetylneuraminic acid as a novel target for therapy in human pre-B acute lymphoblastic leukemia. J Exp Med. 2013;210(4):805-819.

      [Crossref] [Google Scholar]

1356. Barbier V, Erbani J, Fiveash C, Davies JM, Tay J, Tallack MR, et al. Endothelial E-selectin inhibition improves acute myeloid leukaemia therapy by disrupting vascular niche-mediated chemoresistance. Nat Commun. 2020;11(1):2042.

      [Crossref] [Google Scholar] [PubMed]

1357. Muz B, Abdelghafer A, Markovic M, Yavner J, Melam A, Salama NN, et al. Targeting E-selectin to tackle cancer using uproleselan. Cancers. 2021;13(2):335.

      [Crossref] [Google Scholar] [PubMed]

1358. Kobayashi T, Kuroda J, Ashihara E, Oomizu S, Terui Y, Taniyama A, et al. Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways. Leukemia. 2010;24(4):843-850.

      [Crossref] [Google Scholar] [PubMed]

1359. Karube K, Campo E. MYC alterations in diffuse large B-cell lymphomas. Semin Hematol. 2015;52(2):97-106.

      [Crossref] [Google Scholar] [PubMed]

1360. Nguyen L, Papenhausen P, Shao H. The role of c-MYC in B-cell lymphomas: Diagnostic and molecular aspects. Genes. 2017;8(4):116.

      [Crossref] [Google Scholar] [PubMed]

1361. Cai Q, Medeiros LJ, Xu X, Young KH. MYC-driven aggressive B-cell lymphomas: Biology, entity, differential diagnosis and clinical management. Oncotarget. 2015;6(36):38591.

      [Crossref] [Google Scholar] [PubMed]

1362. Li Q, Pan S, Xie T, Liu H. MYC in T-cell acute lymphoblastic leukemia: Functional implications and targeted strategies. Blood Sci. 2021;3(03):65-70.

      [Crossref] [Google Scholar] [PubMed]

1363. Xiao H, Woods EC, Vukojicic P, Bertozzi CR. Precision glycocalyx editing as a strategy for cancer immunotherapy. Proc Natl Acad Sci. 2016;113(37):10304-10309.

      [Crossref] [Google Scholar] [PubMed]

1364. Smith BA, Deutzmann A, Correa KM, Delaveris CS, Dhanasekaran R, Dove CG, et al. MYC-driven synthesis of Siglec ligands is a glycoimmune checkpoint. Proc Natl Acad Sci. 2023;120(11):e2215376120.

      [Crossref] [Google Scholar]

1365. Mikulasova A, Ashby C, Tytarenko RG, Qu P, Rosenthal A, Dent JA, et al. Microhomology-mediated end joining drives complex rearrangements and overexpression of MYC and PVT1 in multiple myeloma. Haematologica. 2020;105(4):1055.

      [Crossref] [Google Scholar] [PubMed]

1366. Duffy MJ, O'Grady S, Tang M, Crown J. MYC as a target for cancer treatment. Cancer Treat Rev. 2021;94:102154.

      [Crossref] [Google Scholar] [PubMed]

1367. Meléndez AV, Velasco Cárdenas RM, Lagies S, Strietz J, Siukstaite L, Thomas OS, et al. Novel lectin-based chimeric antigen receptors target Gb3-positive tumour cells. Cell Mol Life Sci. 2022;79(10):513.

      [Crossref] [Google Scholar] [PubMed]

1368. Sharma P, Zhang X, Ly K, Zhang Y, Hu Y, Ye AY, et al. The lipid globotriaosylceramide promotes germinal center B cell responses and antiviral immunity. Science. 2024;383(6684):eadg0564.

      [Crossref] [Google Scholar] [PubMed]

1369. Yang Z, Hou Y, Grande G, Wang C, Shi Y, Zak J, et al. Enhancing the anti-tumor efficacy of Bispecific T cell engagers via cell surface glycocalyx editing. BioRxiv. 2022:2022.

      [Crossref] [Google Scholar]

1370. Tripodo C, Florena AM, Macor P, Di Bernardo A, Porcasi R, Guarnotta C, et al. P-selectin glycoprotein ligand-1 as a potential target for humoral immunotherapy of multiple myeloma. Curr Cancer Drug Targets. 2009;9(5):617-625.

      [Crossref] [Google Scholar]

1371. Glinsky VV, Raz A. Modified citrus pectin anti-metastatic properties: One bullet, multiple targets. Carbohydr Res. 2009 ;344(14):1788-1791.

      [Crossref] [Google Scholar] [PubMed]

1372. Streetly MJ, Maharaj L, Joel S, Schey SA, Gribben JG, Cotter FE. GCS-100, a novel galectin-3 antagonist, modulates MCL-1, NOXA, and cell cycle to induce myeloma cell death. Blood J Am Soc Hematol. 2010;115(19):3939-3948.

      [Crossref] [Google Scholar] [PubMed]

1373. Thijssen VL, Heusschen R, Caers J, Griffioen AW. Galectin expression in cancer diagnosis and prognosis: A systematic review. Biochim Biophys Acta. 2015;1855(2):235-247.

      [Crossref] [Google Scholar] [PubMed]

1374. Davis RE, Ruvolo VR, Wang Z, Ma W, Schober WD, Rolke J, et al. GCS-100 induces apoptosis of acute myeloid leukemia cells by disrupting galectin-mediated survival signaling. Blood. 2014;124(21):904.

      [Crossref] [Google Scholar] [PubMed]

1375. Chauhan D, Li G, Podar K, Hideshima T, Neri P, He D, et al. A novel carbohydrate-based therapeutic GCS-100 overcomes bortezomib resistance and enhances dexamethasone-induced apoptosis in multiple myeloma cells. Cancer Res. 2005;65(18):8350-8358.

      [Crossref] [Google Scholar] [PubMed]

1376. Cheng CL, Hou HA, Lee MC, Liu CY, Jhuang JY, Lai YJ, et al. Higher bone marrow LGALS3 expression is an independent unfavorable prognostic factor for overall survival in patients with acute myeloid leukemia. Blood J Am Soc Hematol. 2013;121(16):3172-3180.

      [Crossref] [Google Scholar] [PubMed]

1377. Harazono Y, Nakajima K, Raz A. Why anti-Bcl-2 clinical trials fail: A solution. Cancer Metastasis Rev. 2014;33:285-294.

      [Crossref] [Google Scholar] [PubMed]

1378. Aasted MK, Groen AC, Keane JT, Dabelsteen S, Tan E, Schnabel J, et al. Targeting solid cancers with a cancer-specific monoclonal antibody to surface expressed aberrantly O-glycosylated proteins. Mol Cancer Ther. 2023;22(10):1204-1214.

      [Crossref] [Google Scholar] [PubMed]

1379. Tang L, Huang H, Tang Y, Li Q, Wang J, Li D, et al. CD44v6 chimeric antigen receptor T cell specificity towards AML with FLT3 or DNMT3A mutations. Clin Transl Med. 2022;12(9):e1043.

      [Crossref] [Google Scholar] [PubMed]

1380. Vaxevanis CK, Bauer M, Subbarayan K, Friedrich M, Massa C, Biehl K, et al. Biglycan as a mediator of proinflammatory response and target for MDS and sAML therapy. Oncoimmunology. 2023;12(1):2152998.

      [Crossref] [Google Scholar] [PubMed]

1381. Tijink BM, Buter J, De Bree R, Giaccone G, Lang MS, Staab A, et al. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin Cancer Res. 2006;12(20):6064-6072.

      [Crossref] [Google Scholar] [PubMed]

1382. Lodewijk I, Dueñas M, Paramio JM, Rubio C. CD44v6, STn & O-GD2: Promising tumor associated antigens paving the way for new targeted cancer therapies. Front Immunol. 2023;14:1272681.

      [Crossref] [Google Scholar] [PubMed]

1383. Bae J, Accardi F, Hideshima T, Tai YT, Prabhala R, Shambley A, et al. Targeting LAG3/GAL-3 to overcome immunosuppression and enhance anti-tumor immune responses in multiple myeloma. Leukemia. 2022;36(1):138-154.

      [Crossref] [Google Scholar] [PubMed]

1384. El Halabi L, Adam J, Gravelle P, Marty V, Danu A, Lazarovici J, et al. Expression of the immune checkpoint regulators LAG-3 and TIM-3 in classical Hodgkin lymphoma. Clin Lymphoma Myeloma and Leuk. 2021;21(4):257-266.

      [Crossref] [Google Scholar] [PubMed]

1385. Fourcade J, Sun Z, Benallaoua M, Guillaume P, Luescher IF, Sander C, et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med. 2010;207(10):2175-2186.

      [Crossref] [Google Scholar] [PubMed]

1386. Huang RY, Eppolito C, Lele S, Shrikant P, Matsuzaki J, Odunsi K. LAG3 and PD1 co-inhibitory molecules collaborate to limit CD8+ T cell signaling and dampen antitumor immunity in a murine ovarian cancer model. Oncotarget. 2015;6(29):27359.

      [Crossref] [Google Scholar] [PubMed]

1387. Kim JE, Patel MA, Mangraviti A, Kim ES, Theodros D, Velarde E, et al. Combination therapy with anti-PD-1, anti-TIM-3, and focal radiation results in regression of murine gliomas. Clin Cancer Res. 2017;23(1):124-136.

      [Crossref] [Google Scholar] [PubMed]

1388. Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, et al. Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci. 2010;107(17):7875-7880.

      [Crossref] [Google Scholar] [PubMed]

1389. Ngiow SF, Von Scheidt B, Akiba H, Yagita H, Teng MW, Smyth MJ. Anti-TIM3 antibody promotes T cell IFN-γ-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011;71(10):3540-3451.

      [Crossref] [Google Scholar] [PubMed]

1390. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med. 2010;207(10):2187-2194.

      [Crossref] [Google Scholar] [PubMed]

1391. Zhou G, Sprengers D, Boor PP, Doukas M, Schutz H, Mancham S, et al. Antibodies against immune checkpoint molecules restore functions of tumor-infiltrating T cells in hepatocellular carcinomas. Gastroenterology. 2017;153(4):1107-1119.

      [Crossref] [Google Scholar] [PubMed]

1392. Zhou Q, Munger ME, Veenstra RG, Weigel BJ, Hirashima M, Munn DH, et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood J Am Soc Hematol. 2011;117(17):4501-4510.

      [Crossref] [Google Scholar] [PubMed]

1393. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, et al . Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun. 2016;7(1):10501.

      [Crossref] [Google Scholar] [PubMed]

1394. Johnson NA, Lavie D, Borchmann P, Gregory G, Herrera AF, Minuk L, et al. Favezelimab (anti-LAG-3) plus pembrolizumab in patients with anti-PD-1-naive relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL): An open-label phase 1/2 study. JCO. 2022;40:7516.

      [Crossref] [Google Scholar]

1395. Gregory G, Timmerman J, Lavie D, Borchmann P, Herrera AF, Minuk L, et al. P1086: Favezelimab (anti–lag-3) and Pembrolizumab co-blockade in anti-pd-1-naive patients with relapsed or refractory classical Hodgkin lymphoma: An open-label phase 1/2 study. HemaSphere. 2022;6:976-977.

      [Crossref] [Google Scholar]

1396. Herrera AF, Lavie D, Johnson NA, Avigdor A, Borchmann P, Andreadis C, et al. P1087: Favezelimab (Anti-Lag-3) and Pembrolizumab Co-Blockade in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma who Progressed After Anti-Pd-1 Therapy: An Open-Label Phase 1/2 Study. HemaSphere. 2022;6:977-978.

      [Crossref] [Google Scholar]

1397. Corcoran SR, Phelan JD, Choi J, Shevchenko G, Fenner RE, Yu X, et al. Molecular determinants of sensitivity to polatuzumab vedotin in diffuse large B-Cell lymphoma. Cancer Discov 2024;14(9):1653-1674.

      [Crossref] [Google Scholar] [PubMed]

1398. Corcoran SR, Phelan JD, Choi J, Shevchenko G, Fenner RE, Yu X, et al. Molecular determinants of sensitivity to polatuzumab vedotin in diffuse large B-Cell lymphoma. Blood 2023;142: 2819.

      [Crossref] [Google Scholar]

1399. Pang N, Tudahong S, Zhu Y, He J, Han C, Chen G, et al. Galectin‐9 alleviates acute graft‐versus‐host disease after haplo‐hematopoietic stem cell transplantation by regulating regulatory T cell/effector T cell imbalance. Immun InflammDis. 2024;12(2):e1177.

      [Crossref] [Google Scholar] [PubMed]

1400. Li R, Colombo M, Wang G, Rodriguez-Romera A, Benlabiod C, Jooss NJ, et al. A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis. Sci Transl Med. 2024 ;16(768):eadj7552.

      [Crossref] [Google Scholar] [Pubmed]

1401. Krishnamoorthy V, Daly J, Kim J, Piatnitca L, Yuen KA, Kumar B, et al. The glycosyltransferase ST3GAL4 drives immune evasion in acute myeloid leukemia by synthesizing ligands for the glyco-immune checkpoint receptor Siglec-9. Leukemia. 2025 ;39(2):346-359.

      [Crossref] [Google Scholar] [Pubmed]

1402. Falgàs A, Lázaro-Gorines R, Zanetti SR, Rubio-Pérez L, Martínez-Moreno A, Vinyoles M, et al. A TIM-3–Fc decoy secreted by engineered T cells improves CD19 CAR T-cell therapy in B-cell acute lymphoblastic leukemia. Blood. 2025;145(22):2599-2613.

      [Crossref] [Google Scholar] [Pubmed]

1403. Rampotas A, Roddie C. It’s high TIM-3 for armored CAR-T therapy for B-ALL. Blood. 2025;145(22):2538-2540.

      [Crossref] [Google Scholar] [Pubmed]

1404. Schroeder T, Geyh S, Germing U, Haas R. Mesenchymal stromal cells in myeloid malignancies. Blood research. 2016;51(4):225.

      [Crossref] [Google Scholar] [Pubmed]

1405. Vukotić M, Kapor S, Simon F, Cokic V, Santibanez JF. Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities. Heliyon. 2024 15;10(3).

      [Crossref] [Google Scholar] [Pubmed]

1406. Feng J, Gou J, Wang Y, Wei W, Ma Y, Ren X, et al. Bisecting GlcNAc expression by bone marrow stromal cells modulates TGF-β1-driven macrophage polarization in myeloid leukemias. Haematologica. 2020.

      [Crossref] [Google Scholar] [Pubmed]

1407. Ziccheddu B, Giannotta C, D'Agostino M, Bertuglia G, Saraci E, Oliva S, et al. Genomic and immune determinants of resistance to anti-CD38 monoclonal antibody-based therapy in relapsed refractory multiple myeloma. medRxiv. 2023.

      [Crossref] [Google Scholar] [PubMed]

1408. Chen L, Xie T, Wei B, Di DL. Current progress in CAR‑T cell therapy for tumor treatment. Oncol Lett. 2022;24(4):1-2.

      [Crossref] [Google Scholar] [PubMed]

1409. Oliver-Caldes A, Español-Rego M, Zabaleta A, González-Calle V, Navarro-Velázquez S, Inogés S, et al. Biomarkers of efficacy and safety of the academic BCMA-CART ARI0002h for the treatment of refractory multiple myeloma. Clin Cancer Res. 2024;30(10):2085-2096.

      [Crossref] [Google Scholar]

1410. Jain T, Litzow MR. No free rides: Management of toxicities of novel immunotherapies in ALL, including financial. Blood Adv. 2018;2(22):3393-3403.

      [Crossref] [Google Scholar] [PubMed]

1411. Antitumor immunity as the basis for durable disease-free treatment-free survival in patients with metastatic urothelial cancer
1412. Micklethwaite KP, Gowrishankar K, Gloss BS, Li Z, Street JA, Moezzi L, et al. Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells. Blood J Am Soc Hematol. 2021;138(16):1391-1405.

      [Crossref] [Google Scholar] [PubMed]

1413. Harrison SJ, Nguyen T, Rahman M, Er J, Li J, Li K, et al. CAR+ T-cell lymphoma post ciltacabtagene autoleucel therapy for relapsed refractory multiple myeloma. Blood. 2023;142:6939.

      [Crossref] [Google Scholar]

1414. Lamble AJ, Schultz LM, Nguyen K, Hsieh EM, McNerney K, Rouce RH, et al. Risk of T-cell malignancy following CAR T cells in children, adolescents and young adults. Blood Adv. 2024;2024013243.

      [Crossref] [Google Scholar] [PubMed]

1415.  Elsallab M, Ellithi M, Lunning MA, D’Angelo C, Ma J, Perales MA, et al. Second primary malignancies after commercial CAR T-cell therapy: Analysis of the FDA Adverse Events Reporting System. Blood. 2024;143(20):2099-2105.

      [Crossref] [Google Scholar] [PubMed]

1416. Gu T, Zhu M, Huang H, Hu Y. Relapse after CAR-T cell therapy in B-cell malignancies: challenges and future approaches. J Zhejiang Univ Sci B. 2022;23(10):793-811.

      [Crossref] [Google Scholar] [PubMed]

1417. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56.

      [Crossref] [Google Scholar] [PubMed]

1418. Tedone E, Sayed M, Lai TP, Sannareddy A, Ramasamy DP, Anderson Jr LD, et al. T-Cell telomere length as a biomarker to predict outcome in patients receiving CAR-T immunotherapy. Blood. 2021;138:4798.

      [Crossref] [Google Scholar]

1419. Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol. 2019;16(6):372-385.

      [Crossref] [Google Scholar] [PubMed]

1420. Brown CE, Mackall CL. CAR T cell therapy: Inroads to response and resistance. Nat Rev Immunol. 2019;19(2):73-74.

      [Crossref] [Google Scholar] [PubMed]

1421. Reville PK, Sheikh IN, Choi A, Dai E, Henderson J, Li X, et al. CD8 T-cell dysfunction is linked with CAR T-cell failure and can be mitigated by a non-alpha IL-2 agonist, pegenzileukin. bioRxiv. 2023.

      [Crossref] [Google Scholar] [PubMed]

1422. Noh JY, Seo H, Lee J, Jung H. Immunotherapy in hematologic malignancies: Emerging therapies and novel approaches. Int J Mol Sci. 2020;21(21):8000.

      [Crossref] [Google Scholar] [PubMed]

1423. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545-553.

      [Crossref] [Google Scholar] [PubMed]

1424. Li L, Mohanty V, Dou J, Huang Y, Banerjee PP, Miao Q, et al. Loss of metabolic fitness drives tumor resistance after CAR-NK cell therapy and can be overcome by cytokine engineering. Sci Adv. 2023;9(30):eadd6997.

      [Crossref] [Google Scholar] [PubMed]

1425. Li Y, Rezvani K, Rafei H. Next‐generation chimeric antigen receptors for T‐and natural killer‐cell therapies against cancer. Immunol Rev. 2023;320(1):217-235.

      [Crossref] [Google Scholar] [PubMed]

1426. Burke KP, Chaudhri A, Freeman GJ, Sharpe AH. The B7: CD28 family and friends: Unraveling coinhibitory interactions. Immunity. 2024;57(2):223-244.

      [Crossref] [Google Scholar] [PubMed]

1427. Lenza MP, Egia-Mendikute L, Antoñana-Vildosola A, Soares CO, Coelho H, Corzana F, et al. Structural insights into Siglec-15 reveal glycosylation dependency for its interaction with T cells through integrin CD11b. Nat Commun. 2023;14(1):3496.

      [Crossref] [Google Scholar] [PubMed]

1428. Matsumoto Y, Ju T. Aberrant glycosylation as immune therapeutic targets for solid tumors. Cancers. 2023;15(14):3536.

      [Crossref] [Google Scholar] [PubMed]

1429. Houvast RD, Vankemmelbeke M, Durrant LG, Wuhrer M, Baart VM, Kuppen PJ, et al. Targeting glycans and heavily glycosylated proteins for tumor imaging. Cancers. 2020;12(12):3870.

      [Crossref] [Google Scholar] [PubMed]

1430. Stowell SR, Ju T, Cummings RD. Protein glycosylation in cancer. Annu Rev Pathol. 2015;10(1):473-510.

      [Crossref] [Google Scholar] [PubMed]

1431. Nabi-Afjadi M, Heydari M, Zalpoor H, Arman I, Sadoughi A, Sahami P, et al. Lectins and lectibodies: Potential promising antiviral agents. Cell Mol Biol Lett. 2022;27(1):37.

      [Crossref] [Google Scholar] [PubMed]

1432. Hamorsky KT, Kouokam JC, Dent MW, Grooms TN, Husk AS, Hume SD, et al. Engineering of a lectibody targeting high-mannose-type glycans of the HIV envelope. Mol Ther. 2019;27(11):2038-2052.

      [Crossref] [Google Scholar] [PubMed]

1433. Khilji SK, Goerdeler F, Frensemeier K, Warschkau D, Lühle J, Fandi Z, et al. Generation of glycan-specific nanobodies. Cell Chem Biol. 2022;29(8):1353-1361.

      [Crossref] [Google Scholar] [PubMed]

1434. Choi Y, Kim J, Chae J, Hong J, Park J, Jeong E, et al. Surface glycan targeting for cancer nano-immunotherapy. J  Control Release. 2022;342:321-336.

      [Crossref] [Google Scholar] [PubMed]

1435. Gupta A, Yadav K, Yadav A, Ahmad R, Srivastava A, Kumar D, et al. Mannose-specific plant and microbial lectins as antiviral agents: A review. Glycoconj J. 2024;41(1):1-33.

      [Crossref] [Google Scholar] [PubMed]

1436. Saad AA. Targeting cancer-associated glycans as a therapeutic strategy in leukemia. All Life. 2022;15(1):378-433.

      [Crossref] [Google Scholar]

1437. Salanti A, Clausen TM, Agerbæk MØ, Al Nakouzi N, Dahlbäck M, Oo HZ, et al. Targeting human cancer by a glycosaminoglycan binding malaria protein. Cancer Cell. 2015;28(4):500-514.

      [Crossref] [Google Scholar] [PubMed]

1438. Spliid CB, Toledo AG, Sanderson P, Mao Y, Gatto F, Gustavsson T, et al. The specificity of the malarial VAR2CSA protein for chondroitin sulfate depends on 4-O-sulfation and ligand accessibility. J Biol Chem. 2021;297(6).

      [Crossref] [Google Scholar] [PubMed]

1439. Harrer DC, Schuler G, Dörrie J, Schaft N. CSPG4-specific CAR T cells for high-risk childhood B cell precursor leukemia. Int J Mol Sci. 2019;20(11):2764.

      [Crossref] [Google Scholar] [PubMed]

1440. Fernandes E, Sores J, Cotton S, Peixoto A, Ferreira D, Freitas R, et al. Esophageal, gastric and colorectal cancers: Looking beyond classical serological biomarkers towards glycoproteomics-assisted precision oncology. Theranostics. 2020;10(11):4903.

      [Crossref] [Google Scholar] [PubMed]

1441. He K, Baniasad M, Kwon H, Caval T, Xu G, Lebrilla C, et al. Decoding the glycoproteome: A new frontier for biomarker discovery in cancer. J Hematol Oncol. 2024;17(1):12.

      [Crossref] [Google Scholar] [PubMed]

1442.  Hara-Yokoyama M, Kukimoto-Niino M, Terasawa K, Harumiya S, Podyma-Inoue KA, Hino N, et al. Tetrameric interaction of the ectoenzyme CD38 on the cell surface enables its catalytic and raft-association activities. Structure. 2012;20(9):1585-1595.

      [Crossref] [Google Scholar] [PubMed]

1443. Gao Y, Mehta K. N-linked glycosylation of CD38 is required for its structure stabilization but not for membrane localization. Mol Cell Biochem. 2007;295:1-7.

      [Crossref] [Google Scholar] [PubMed]

1444. Heard A, Landmann JH, Hansen AR, Papadopolou A, Hsu YS, Selli ME, et al. Antigen glycosylation regulates efficacy of CAR T cells targeting CD19. Nat Commun. 2022;13(1):3367.

      [Crossref] [Google Scholar] [PubMed]

1445. Bartish M, Del Rincón SV, Rudd CE, Saragovi HU. Aiming for the sweet spot: Glyco-immune checkpoints and γδ T cells in targeted immunotherapy. Front Immunol. 2020;11:564499.

      [Crossref] [Google Scholar] [PubMed]

1446. Derosiers N, Aguilar W, DeGaramo DA, Posey AD. Sweet immune checkpoint targets to enhance T cell therapy. J Immunol. 2022;208(2):278-285.

      [Crossref] [Google Scholar] [PubMed]

1447. Adams OJ, Stanczak MA, von Gunten S, Läubli H. Targeting sialic acid-siglec interactions to reverse immune suppression in cancer. Glycobiology. 2018;28(9):640-647.

      [Crossref] [Google Scholar] [PubMed]

1448. Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SE, Gregory CD, et al. An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade. Cancer Res. 2019;79(7):1480-1492.

      [Crossref] [Google Scholar] [PubMed]

1449. Mereiter S, Jonsson G, Oliveira T, Helm J, Hoffmann D, Abeln M, et al. Tumor sialylation controls effective anti-cancer immunity in breast cancer. bioRxiv. 2023.

      [Crossref] [Google Scholar]

1450. Stanczak MA, Rodrigues Mantuano N, Kirchhammer N, Sanin DE, Jacob F, Coelho R, et al. Targeting cancer glycosylation repolarizes tumor-associated macrophages allowing effective immune checkpoint blockade. Sci Transl Med. 2022;14(669):eabj1270.

      [Crossref] [Google Scholar] [PubMed]

1451. Gray MA, Stanczak MA, Mantuano NR, Xiao H, Pijnenborg JF, Malaker SA, et al. Targeted glycan degradation potentiates the anticancer immune response in vivo. Nature chemical biology. 2020;16(12):1376-1384.

      [Crossref] [Google Scholar] [PubMed]

1452. Szijj PA, Gray MA, Ribi MK, Bahou C, Nogueira JC, Bertozzi CR, et al. Chemical generation of checkpoint inhibitory T cell engagers for the treatment of cancer. Nat Chem. 2023;15(11):1636-1647.

      [Crossref] [Google Scholar] [PubMed]

1453. Ales E, Sackstein R. The biology of E-selectin ligands in leukemogenesis. Adv Cancer Res. 2023;157:229-250.

      [Crossref] [Google Scholar] [PubMed]

1454. Rodriguez E. Tumor glycosylation: a main player in the modulation of immune responses. European Journal of Immunology. 2025;55(3):e202451318.

      [Crossref] [Google Scholar] [PubMed]

1455. Cummings RD. The repertoire of glycan determinants in the human glycome. Mol BioSyst. 2009;5(10):1087-1104.

      [Crossref] [Google Scholar] [PubMed]