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ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism

Author

Listed:
  • Jie Li

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill)

  • Phillip M. Galbo

    (Albert Einstein College of Medicine)

  • Weida Gong

    (University of North Carolina at Chapel Hill School of Medicine)

  • Aaron J. Storey

    (University of Arkansas for Medical Sciences)

  • Yi-Hsuan Tsai

    (University of North Carolina at Chapel Hill School of Medicine)

  • Xufen Yu

    (Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Jeong Hyun Ahn

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Yiran Guo

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill)

  • Samuel G. Mackintosh

    (University of Arkansas for Medical Sciences)

  • Ricky D. Edmondson

    (University of Arkansas for Medical Sciences)

  • Stephanie D. Byrum

    (University of Arkansas for Medical Sciences)

  • Jason E. Farrar

    (Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute)

  • Shenghui He

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Ling Cai

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine)

  • Jian Jin

    (Mount Sinai Center for Therapeutics Discovery, Departments of Pharmacological Sciences and Oncological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai)

  • Alan J. Tackett

    (University of Arkansas for Medical Sciences
    Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences and Arkansas Children’s Research Institute)

  • Deyou Zheng

    (Albert Einstein College of Medicine
    Albert Einstein College of Medicine)

  • Gang Greg Wang

    (University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill School of Medicine
    University of North Carolina at Chapel Hill)

Abstract

Recurring chromosomal translocation t(10;17)(p15;q21) present in a subset of human acute myeloid leukemia (AML) patients creates an aberrant fusion gene termed ZMYND11-MBTD1 (ZM); however, its function remains undetermined. Here, we show that ZM confers primary murine hematopoietic stem/progenitor cells indefinite self-renewal capability ex vivo and causes AML in vivo. Genomics profilings reveal that ZM directly binds to and maintains high expression of pro-leukemic genes including Hoxa, Meis1, Myb, Myc and Sox4. Mechanistically, ZM recruits the NuA4/Tip60 histone acetyltransferase complex to cis-regulatory elements, sustaining an active chromatin state enriched in histone acetylation and devoid of repressive histone marks. Systematic mutagenesis of ZM demonstrates essential requirements of Tip60 interaction and an H3K36me3-binding PWWP (Pro-Trp-Trp-Pro) domain for oncogenesis. Inhibitor of histone acetylation-‘reading’ bromodomain proteins, which act downstream of ZM, is efficacious in treating ZM-induced AML. Collectively, this study demonstrates AML-causing effects of ZM, examines its gene-regulatory roles, and reports an attractive mechanism-guided therapeutic strategy.

Suggested Citation

  • Jie Li & Phillip M. Galbo & Weida Gong & Aaron J. Storey & Yi-Hsuan Tsai & Xufen Yu & Jeong Hyun Ahn & Yiran Guo & Samuel G. Mackintosh & Ricky D. Edmondson & Stephanie D. Byrum & Jason E. Farrar & Sh, 2021. "ZMYND11-MBTD1 induces leukemogenesis through hijacking NuA4/TIP60 acetyltransferase complex and a PWWP-mediated chromatin association mechanism," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21357-3
    DOI: 10.1038/s41467-021-21357-3
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    Cited by:

    1. Sonali Narang & Yohana Ghebrechristos & Nikki A. Evensen & Nina Murrell & Sylwia Jasinski & Talia H. Ostrow & David T. Teachey & Elizabeth A. Raetz & Timothee Lionnet & Matthew Witkowski & Iannis Aifa, 2024. "Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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