Journal of Leukemia
Open Access

The Bone Marrow Microenvironment in Leukemia: From Sanctuary to Therapeutic Target

Julia Weber^{* *}Correspondence: Julia Weber, Department of Cancer Biology, Karolinska Institutet, Stockholm, Sweden, Email:

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Description

The bone marrow microenvironment has emerged as a critical determinant of leukemia pathogenesis, progression, and therapeutic resistance. Once viewed as merely a passive sanctuary for leukemic cells, this complex ecosystem is now recognized as an active participant in the leukemic process, engaging in bidirectional interactions that support malignant cell survival and proliferation while subverting normal hematopoiesis. This evolving understanding has profound implications for therapeutic approaches, suggesting that effective leukemia eradication may require targeting not only the malignant cells but also their supportive microenvironment. 

The bone marrow niche comprises diverse cellular components, including mesenchymal stromal cells, endothelial cells, adipocytes, osteoblasts, and various immune cell populations, all embedded within an extracellular matrix rich in cytokines, growth factors, and adhesion molecules. In normal hematopoiesis, this microenvironment provides critical signals that regulate stem cell self-renewal, differentiation, and mobilization. In leukemia, however, these same interactions are subverted to promote malignant cell survival and resistance to therapy. 

Leukemic cells actively remodel their microenvironment through multiple mechanisms. They secrete pro-inflammatory cytokines that alter the function of surrounding stromal cells, induce the expansion of immunosuppressive cell populations, and disrupt normal hematopoietic niches. This remodeling creates a permissive environment for leukemic cell engraftment and expansion while simultaneously suppressing normal hematopoiesis. For instance, Acute Myeloid Leukemia (AML) blasts have been shown to induce functional changes in mesenchymal stromal cells, reprogramming them to preferentially support leukemic over normal hematopoietic progenitors through altered secretion of growth factors and cytokines. Adhesion-mediated interactions between leukemic cells and stromal components play a crucial role in therapy resistance. The binding of leukemic cells to fibronectin, laminin, and other extracellular matrix proteins through integrins activates pro-survival signaling pathways and confers protection against chemotherapy-induced apoptosis, a phenomenon known as Cell Adhesion-Mediated Drug Resistance (CAM-DR). Similarly, direct cell-cell interactions between leukemic cells and mesenchymal stromal cells or endothelial cells can promote survival through the activation of pathways. These protective mechanisms contribute to minimal residual disease and eventual relapse despite apparent initial responses to therapy.

The hypoxic nature of the bone marrow microenvironment represents another dimension of its influence on leukemic biology. Oxygen gradients within the marrow create variably hypoxic niches that can affect leukemic cell metabolism, genomic stability, and therapeutic sensitivity. Hypoxia-Inducible Factors (HIFs) are upregulated in response to low oxygen tension and orchestrate adaptive responses that promote leukemic cell survival. These include metabolic reprogramming toward glycolysis, increased production of reactive oxygen species, and upregulation of drug efflux transporters. The preferential location of leukemic stem cells in hypoxic regions may contribute to their resistance to conventional therapies and persistence as disease-initiating reservoirs.

Immune evasion within the bone marrow microenvironment represents a significant obstacle to effective leukemia control. Leukemic cells can induce an immunosuppressive milieu through multiple mechanisms, including the recruitment and expansion of regulatory T cells and myeloid-derived suppressor cells, the expression of immune checkpoint molecules such as PD-L1, and the secretion of immunomodulatory cytokines like TGF-β and IL-10. These adaptations effectively shield leukemic cells from immune surveillance and limit the efficacy of immunotherapeutic approaches. Understanding and targeting these immune evasion strategies represents a critical challenge in leveraging the immune system for leukemia control.