Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia

• Published in: Cell death & disease Vol. 10; no. 10; pp. 736 - 14
• Main Authors: Ganesan, Saravanan, Palani, Hamenth Kumar, Lakshmanan, Vairavan, Balasundaram, Nithya, Alex, Ansu Abu, David, Sachin, Venkatraman, Arvind, Korula, Anu, George, Biju, Balasubramanian, Poonkuzhali, Palakodeti, Dasaradhi, Vyas, Neha, Mathews, Vikram
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.09.2019; Springer Nature B.V
• Subjects: 13; 13/89; 38/90; 38/91; 631/67/1990/283/1897; 631/67/327; 96/1; 96/2; 96/31; Acute myeloid leukemia; Adjuvants; Animals; Antibodies; Apoptosis; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Autophagy - genetics; Biochemistry; Biomedical and Life Sciences; Bone marrow; Bone Marrow Cells - drug effects; Cell Biology; Cell Culture; Chemotherapy; Daunorubicin - pharmacology; Drug resistance; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Immunology; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Life Sciences; Male; Mice; MicroRNAs - genetics; Minimal residual disease; miRNA; Myeloid leukemia; Neoplasm, Residual - genetics; Neoplasm, Residual - pathology; Phagocytosis; Stromal cells; Stromal Cells - drug effects; Stromal Cells - pathology; TLR2 protein; Toll-Like Receptor 2 - drug effects; Toll-like receptors; Tumor Microenvironment - drug effects; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-1964-8

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.