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

Overview

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.

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

publication date

  • September 30, 2019

Research

keywords

  • Autophagy
  • Leukemia, Myeloid, Acute
  • MicroRNAs
  • Stromal Cells
  • Toll-Like Receptor 2

Identity

PubMed Central ID

  • PMC6769009

Scopus Document Identifier

  • 85072769138

Digital Object Identifier (DOI)

  • 10.1038/s41419-019-1964-8

PubMed ID

  • 31570693

Additional Document Info

volume

  • 10

issue

  • 10