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BRD4-mediated repression of p53 is a target for combination therapy in AML

Author

Listed:
  • Anne-Louise Latif

    (University of Glasgow)

  • Ashley Newcombe

    (University of Glasgow)

  • Sha Li

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Kathryn Gilroy

    (University of Glasgow)

  • Neil A. Robertson

    (University of Glasgow)

  • Xue Lei

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Helen J. S. Stewart

    (University of Sussex)

  • John Cole

    (University of Glasgow)

  • Maria Terradas Terradas

    (University of Glasgow)

  • Loveena Rishi

    (University of Glasgow)

  • Lynn McGarry

    (Cancer Research UK Beatson Institute)

  • Claire McKeeve

    (Queen Elizabeth University Hospital)

  • Claire Reid

    (University of Glasgow)

  • William Clark

    (Cancer Research UK Beatson Institute)

  • Joana Campos

    (College of Medical Veterinary and Life Sciences, University of Glasgow)

  • Kristina Kirschner

    (University of Glasgow)

  • Andrew Davis

    (Sanford Burnham Prebys Medical Discovery Institute)

  • Jonathan Lopez

    (University of Glasgow)

  • Jun-ichi Sakamaki

    (Cancer Research UK Beatson Institute)

  • Jennifer P. Morton

    (University of Glasgow
    Cancer Research UK Beatson Institute)

  • Kevin M. Ryan

    (Cancer Research UK Beatson Institute)

  • Stephen W. G. Tait

    (University of Glasgow)

  • Sheela A. Abraham

    (College of Medical Veterinary and Life Sciences, University of Glasgow
    Queen’s University)

  • Tessa Holyoake

    (College of Medical Veterinary and Life Sciences, University of Glasgow)

  • Brian Higgins

    (Roche Innovation Center-New York)

  • Xu Huang

    (College of Medical Veterinary and Life Sciences, University of Glasgow)

  • Karen Blyth

    (University of Glasgow
    Cancer Research UK Beatson Institute)

  • Mhairi Copland

    (College of Medical Veterinary and Life Sciences, University of Glasgow)

  • Timothy J. T. Chevassut

    (University of Sussex)

  • Karen Keeshan

    (College of Medical Veterinary and Life Sciences, University of Glasgow)

  • Peter D. Adams

    (University of Glasgow
    Sanford Burnham Prebys Medical Discovery Institute)

Abstract

Acute myeloid leukemia (AML) is a typically lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually, most AML retain wild-type TP53, encoding the pro-apoptotic tumor suppressor p53. MDM2 inhibitors (MDM2i), which activate wild-type p53, and BET inhibitors (BETi), targeting the BET-family co-activator BRD4, both show encouraging pre-clinical activity, but limited clinical activity as single agents. Here, we report enhanced toxicity of combined MDM2i and BETi towards AML cell lines, primary human blasts and mouse models, resulting from BETi’s ability to evict an unexpected repressive form of BRD4 from p53 target genes, and hence potentiate MDM2i-induced p53 activation. These results indicate that wild-type TP53 and a transcriptional repressor function of BRD4 together represent a potential broad-spectrum synthetic therapeutic vulnerability for AML.

Suggested Citation

  • Anne-Louise Latif & Ashley Newcombe & Sha Li & Kathryn Gilroy & Neil A. Robertson & Xue Lei & Helen J. S. Stewart & John Cole & Maria Terradas Terradas & Loveena Rishi & Lynn McGarry & Claire McKeeve , 2021. "BRD4-mediated repression of p53 is a target for combination therapy in AML," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20378-8
    DOI: 10.1038/s41467-020-20378-8
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