TY - JOUR T1 - Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia. JF - Cell Death Dis Y1 - 2019 A1 - Ganesan, Saravanan A1 - Palani, Hamenth Kumar A1 - Lakshmanan, Vairavan A1 - Balasundaram, Nithya A1 - Alex, Ansu Abu A1 - David, Sachin A1 - Venkatraman, Arvind A1 - Korula, Anu A1 - George, Biju A1 - Balasubramanian, Poonkuzhali A1 - Palakodeti, Dasaradhi A1 - Vyas, Neha A1 - Mathews, Vikram AB -

Complex molecular cross talk between stromal cells and the leukemic cells in bone marrow is known to contribute significantly towards drug-resistance. Here, we have identified the molecular events that lead to stromal cells mediated therapy-resistance in acute myeloid leukemia (AML). Our work demonstrates that stromal cells downregulate miR-23a-5p levels in leukemic cells to protect them from the chemotherapy induced apoptosis. Downregulation of miR-23a-5p in leukemic cells leads to upregulation of protective autophagy by targeting TLR2 expression. Further, autophagy inhibitors when used as adjuvants along with conventional drugs can improve drug sensitivity in vitro as well in vivo in a mouse model of leukemia. Our work also demonstrates that this mechanism of bone marrow stromal cell mediated regulation of miR-23a-5p levels and subsequent molecular events are relevant predominantly in myeloid leukemia. Our results illustrate the critical and dynamic role of the bone marrow microenvironment in modulating miRNA expression in leukemic cells which could contribute significantly to drug resistance and subsequent relapse, possibly through persistence of minimal residual disease in this environment.

VL - 10 IS - 10 ER -