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The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia

Author

Listed:
  • Akihiko Numata

    (National University of Singapore)

  • Hui Si Kwok

    (National University of Singapore)

  • Akira Kawasaki

    (National University of Singapore)

  • Jia Li

    (National University of Singapore)

  • Qi-Ling Zhou

    (National University of Singapore)

  • Jon Kerry

    (University of Oxford)

  • Touati Benoukraf

    (National University of Singapore)

  • Deepak Bararia

    (National University of Singapore)

  • Feng Li

    (National University of Singapore)

  • Erica Ballabio

    (University of Oxford)

  • Marta Tapia

    (University of Oxford)

  • Aniruddha J. Deshpande

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Robert S. Welner

    (Comprehensive Cancer Center)

  • Ruud Delwel

    (Erasmus University Medical Center)

  • Henry Yang

    (National University of Singapore)

  • Thomas A. Milne

    (University of Oxford)

  • Reshma Taneja

    (National University of Singapore)

  • Daniel G. Tenen

    (National University of Singapore
    Harvard Medical School)

Abstract

Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.

Suggested Citation

  • Akihiko Numata & Hui Si Kwok & Akira Kawasaki & Jia Li & Qi-Ling Zhou & Jon Kerry & Touati Benoukraf & Deepak Bararia & Feng Li & Erica Ballabio & Marta Tapia & Aniruddha J. Deshpande & Robert S. Weln, 2018. "The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03854-0
    DOI: 10.1038/s41467-018-03854-0
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