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.