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.

已知骨髓中基质细胞和白血病细胞之间复杂的分子串扰对耐药性有显着贡献。在这里，我们确定了导致急性髓系白血病（AML）中基质细胞介导的治疗耐药的分子事件。我们的工作表明，基质细胞下调白血病细胞中的miR-23a-5p水平，以保护它们免受化疗诱导的细胞凋亡。白血病细胞中miR-23a-5p的下调通过靶向 TLR2 表达导致保护性自噬上调。此外，自噬抑制剂与常规药物一起用作佐剂时，可以提高白血病小鼠模型的体外和体内药物敏感性。我们的工作还表明，骨髓基质细胞介导的miR-23a-5p水平调节和随后的分子事件的这种机制主要与骨髓性白血病相关。我们的结果说明了骨髓微环境在调节白血病细胞中 miRNA 表达中的关键和动态作用，这可能对耐药性和随后的复发有显着贡献，可能是通过该环境中微小残留病的持续存在。