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

Abstract

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 microenviron-ment (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. Plain Language Summary: Acute Myeloid Leukemia (AML) is an aggressive blood cancer. It occurs when immature cells build up in the bone marrow, the soft tissue inside your bones where the body makes new blood. While many people respond well to initial treatment, the disease often returns because some AML cells survive by "hijacking" their surroundings. This review explains how AML cells attach themselves to healthy bone marrow structures and send out chemical signals that force nearby healthy cells to protect them. This creates a shield that hides the cancer from both chemotherapy and the body's own immune system. Importantly, the review explores how we can target this communication to prevent the disease from returning. A major challenge remains the difficulty of accurately modeling this complex environment in the laboratory. Current models often struggle to mimic the complex human bone marrow, which is why many drugs that appear promising in tests fail to help people in clinical trials. Therefore, the review highlights the need to use advanced models which allow researchers to more reliably test new strategies to disrupt the protective bone marrow environment. The review concludes that the bone marrow acts as a single, connected shield rather than separate pieces. Because these parts work together to protect the cancer, blocking just one pathway is often not enough. Overcoming resistance requires new strategies that simultaneously target the leukemia cells and the multiple parts of the environment that support them.