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miR-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective RAB27B targeting to inhibit exosome shedding

Leukemiavolume 32pages11801188 (2018) | Download Citation

Abstract

Leukemia stem cells (LSCs) are responsible for acute myeloid leukemia (AML) chemotherapy resistance and relapse. Here, we discovered that miR-34c-5p, a microRNA central to the senescence regulation network, was significantly down-regulated in AML (non-acute promyelocytic leukemia, non-APL) stem cells compared to that in normal hematopoietic stem cells (HSCs). The lower expression of miR-34c-5p in LSCs was closely correlated to the adverse prognosis and poor responses to therapy of AML patients. Increased miR-34c-5p expression induced LSCs senescence ex vivo, prevented leukemia development and promoted the eradication of LSCs in immune deficient mice. Mechanistically, forced expression of miR-34-5p induced senescence in LSCs through p53-p21Cip1-Cyclin-dependent kinase (CDK)/Cyclin or p53-independent CDK/Cyclin pathways. Exosome-mediated transfer of miR-34c-5p was one of the reasons for miR-34c-5p deficiency in LSCs. Furthermore, miR-34c-5p could increase its intracellular level by inhibiting exosome-mediated transfer via a positive feedback loop through RAB27B, a molecule that promotes exosome shedding. Overall, this study establishes a new strategy for treatment of AML patients by targeting LSCs to reinitiate senescence via increased miR-34c-5p expression. This miRNA-mediated tumor stem cell senescence could also have important therapeutic value in other malignancies.

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Acknowledgements

This project was supported by grants from the National Natural Science Foundation of China (Nos. 81370660, 81770192, 81300412).

Author contributions

DP performed experiments, analyzed the data, and wrote the manuscript; HW, XM, and YC gathered biological samples and provided great help with mouse experiments; YL, YX, and LL conceived the study, analyzed the data and wrote the manuscript; LL and ZH provided critical evaluation of experimental data and the manuscript.

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Author notes

  1. Danyue Peng, Huifang Wang and Lei Li contributed equally to this work.

Affiliations

  1. Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    • Danyue Peng
    • , Huifang Wang
    • , Xiao Ma
    • , Ying Chen
    • , Hao Zhou
    •  & Lingbo Liu
  2. Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    • Lei Li
  3. Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430000, China

    • Yi Luo
  4. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    • Yin Xiao

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The authors declare that they have no conflict of interest.

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Correspondence to Yi Luo or Yin Xiao or Lingbo Liu.

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DOI

https://doi.org/10.1038/s41375-018-0015-2