The role of the bone marrow microenvironment in leukemic stem cell resistance: Pathways of persistence and selection

: Chronic Myeloid Leukemia is driven by the BCR::ABL1 fusion gene, which transforms bone marrow stem cells. Tyrosine kinase inhibitors have markedly improved patients' outcomes. However, only about 20 % of patients are cured, remaining free of relapses after the achievement of a profound and durable molecular remission of the disease and the suspension of tyrosine kinase inhibitors. In most cases, leukemic stem cells persist and contribute to disease relapse after treatment suspension or the development of acquired resistance to tyrosine kinase inhibitors. Emerging evidence underscores the pivotal role of the bone marrow microenvironment in sustaining leukemic stem cells and contributing to drug resistance. Stromal progenitor cells within the bone marrow niche play a key role in supporting the persistence and survival of resistant leukemic stem cells. This review examines how the bone marrow microenvironment and its components promote drug resistance through mechanisms such as metabolic reprogramming, aberrant signaling, and protective cellular interactions. These insights reveal potential therapeutic strategies aimed at disrupting the leukemic stem cell supportive niche to achieve more effective eradication of resistant clones. Understanding the complex interplay between leukemic stem cells and their microenvironment is crucial for developing targeted treatments that can overcome resistance and achieve long-term remission in patients with chronic myeloid leukemia.