Role of the bone marrow vascular niche in chemotherapy for MLL-AF9-induced acute myeloid leukemia

Abstract

Leukemia stem cells in acute myeloid leukemia (AML) can persist within unique bone marrow niches similar to those of healthy hematopoietic stem cells and resist chemotherapy. In the context of AML, endothelial cells (ECs) are crucial components of these niches that appear to promote malignant expansion despite treatment. To better understand these interactions, we developed a real-time cell cycle-tracking mouse model of AML (Fucci-MA9) with an aim of unraveling why quiescent leukemia cells are more resistant to chemotherapy than cycling cells and proliferate during disease relapse. We found that quiescent leukemia cells were more prone to escape chemotherapy than cycling cells, leading to relapse and proliferation. Importantly, post-chemotherapy resting leukemia cells tended to localize closer to blood vessels. Mechanistically, after chemotherapy, resting leukemia cells interacted with ECs, promoting their adhesion and anti-apoptotic capacity. Further, expression analysis of ECs and leukemia cells during AML, after chemotherapy, and after relapse revealed the potential of suppressing the post-chemotherapy inflammatory response to regulate the functions of leukemia cells and ECs. These findings highlight the role of leukemia cells in evading chemotherapy by seeking refuge near blood vessels and provide important insights and directions for future AML research and treatment.

Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression

“…Most importantly, these EC-fused AML cells retain the ability to trigger a full-blown relapse upon transplantation, illustrating their potential to act as a hidden reservoir of residual disease. Interestingly, Xu et al [189] have recently shown in an MLL-AF9 AML mouse model that nearly half of AML blasts in resting phase were observed within 0 to 4 µm from blood vessels, suggesting that quiescent leukaemic cells make cell-cell contact with ECs to evade therapy. Indeed, several mRNAs associated with the development of leukaemia, including Dusp6, Klf4, and Plxnb2, were significantly elevated in ECs and resting leukaemia cells after chemotherapy.…”