Exploring the Bone Marrow Microenvironment as a Therapeutic Barrier and Targetable Source of Crosstalk in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive and genetically heterogeneous hematological malignancy characterized by the accumulation of immature myeloid blasts that disrupt healthy hematopoiesis. Despite advances in molecular profiling and targeted therapies, overcoming drug resistance and relapse remains a significant clinical challenge, resulting in poor long-term outcomes. Crucially, disease persistence is sustained not merely by intrinsic genetic lesions but by a highly adaptive bone marrow microenvironment (BMME) that functions as a therapeutic barrier. While the healthy niche tightly regulates hematopoietic stem cell maintenance, leukemic blasts co-opt stromal, vascular, and immune components to establish a sanctuary that fuels proliferation and shields the disease from cytotoxic stress. However, dissecting these reciprocal dependency mechanisms uncovers critical vulnerabilities, presenting a vital opportunity to develop novel targeted therapies. In this review, we discuss the architecture of the healthy BMME and its pathological AML-driven remodeling. We describe the role of specific signaling axes that govern AML-BMME crosstalk and evaluate targeted therapeutic strategies designed to uncouple these protective interactions. Finally, we highlight that current preclinical models lack the complexity of the BMME stromal components and its spatial organization, a limitation that continues to hinder clinical translation and delay the development of effective combination therapies.