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Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance

Author

Listed:
  • Lianjun Zhang

    (City of Hope Medical Center)

  • Le Xuan Truong Nguyen

    (City of Hope Medical Center)

  • Ying-Chieh Chen

    (City of Hope Medical Center)

  • Dijiong Wu

    (First Affiliated Hospital of Zhejiang Chinese Medical University)

  • Guerry J. Cook

    (City of Hope Medical Center)

  • Dinh Hoa Hoang

    (City of Hope Medical Center)

  • Casey J. Brewer

    (City of Hope Medical Center)

  • Xin He

    (City of Hope Medical Center)

  • Haojie Dong

    (City of Hope Medical Center)

  • Shu Li

    (Zhejiang University School of Medicine)

  • Man Li

    (City of Hope Medical Center)

  • Dandan Zhao

    (City of Hope Medical Center)

  • Jing Qi

    (City of Hope Medical Center)

  • Wei-Kai Hua

    (City of Hope Medical Center)

  • Qi Cai

    (City of Hope Medical Center)

  • Emily Carnahan

    (City of Hope Medical Center)

  • Wei Chen

    (City of Hope Medical Center)

  • Xiwei Wu

    (City of Hope Medical Center)

  • Piotr Swiderski

    (City of Hope Medical Center)

  • Russell C. Rockne

    (City of Hope Medical Center)

  • Marcin Kortylewski

    (City of Hope Medical Center)

  • Ling Li

    (City of Hope Medical Center)

  • Bin Zhang

    (City of Hope Medical Center)

  • Guido Marcucci

    (City of Hope Medical Center)

  • Ya-Huei Kuo

    (City of Hope Medical Center)

Abstract

Acute myeloid leukemia (AML) harboring inv(16)(p13q22) expresses high levels of miR-126. Here we show that the CBFB-MYH11 (CM) fusion gene upregulates miR-126 expression through aberrant miR-126 transcription and perturbed miR-126 biogenesis via the HDAC8/RAN-XPO5-RCC1 axis. Aberrant miR-126 upregulation promotes survival of leukemia-initiating progenitors and is critical for initiating and maintaining CM-driven AML. We show that miR-126 enhances MYC activity through the SPRED1/PLK2-ERK-MYC axis. Notably, genetic deletion of miR-126 significantly reduces AML rate and extends survival in CM knock-in mice. Therapeutic depletion of miR-126 with an anti-miR-126 (miRisten) inhibits AML cell survival, reduces leukemia burden and leukemia stem cell (LSC) activity in inv(16) AML murine and xenograft models. The combination of miRisten with chemotherapy further enhances the anti-leukemia and anti-LSC activity. Overall, this study provides molecular insights for the mechanism and impact of miR-126 dysregulation in leukemogenesis and highlights the potential of miR-126 depletion as a therapeutic approach for inv(16) AML.

Suggested Citation

  • Lianjun Zhang & Le Xuan Truong Nguyen & Ying-Chieh Chen & Dijiong Wu & Guerry J. Cook & Dinh Hoa Hoang & Casey J. Brewer & Xin He & Haojie Dong & Shu Li & Man Li & Dandan Zhao & Jing Qi & Wei-Kai Hua , 2021. "Targeting miR-126 in inv(16) acute myeloid leukemia inhibits leukemia development and leukemia stem cell maintenance," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26420-7
    DOI: 10.1038/s41467-021-26420-7
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    1. Matteo Maria Naldini & Gabriele Casirati & Matteo Barcella & Paola Maria Vittoria Rancoita & Andrea Cosentino & Carolina Caserta & Francesca Pavesi & Erika Zonari & Giacomo Desantis & Diego Gilioli & , 2023. "Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Matteo Marchesini & Andrea Gherli & Elisa Simoncini & Lucas Moron Dalla Tor & Anna Montanaro & Natthakan Thongon & Federica Vento & Chiara Liverani & Elisa Cerretani & Anna D’Antuono & Luca Pagliaro &, 2024. "Orthogonal proteogenomic analysis identifies the druggable PA2G4-MYC axis in 3q26 AML," Nature Communications, Nature, vol. 15(1), pages 1-22, December.

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