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Cell Death Dis. 2019 Sep 30;10(10):736. doi: 10.1038/s41419-019-1964-8.

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

Author information

1
Department of Haematology, Christian Medical College, Vellore, India.
2
Institute for Stem Cell Biology and Regenerative Medicine (InStem), Bengaluru, India.
3
Molecular Medicine Department, St. John's Research Institute, St. John's National Academy of Health Sciences, Bengaluru, India. neha.v@sjri.res.in.
4
Department of Haematology, Christian Medical College, Vellore, India. vikram@cmcvellore.ac.in.

Abstract

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.

PMID:
31570693
DOI:
10.1038/s41419-019-1964-8
Free PMC Article

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