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Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells

Author

Listed:
  • Sheela A. Abraham

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Lisa E. M. Hopcroft

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Emma Carrick

    (Stem Cell and Leukaemia Proteomics laboratory, University of Manchester
    Manchester Precision Medicine Institute, University of Manchester)

  • Mark E. Drotar

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Karen Dunn

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Andrew J. K. Williamson

    (Stem Cell and Leukaemia Proteomics laboratory, University of Manchester
    Manchester Precision Medicine Institute, University of Manchester)

  • Koorosh Korfi

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital
    Institute of Cancer Sciences, University of Glasgow)

  • Pablo Baquero

    (Institute of Cancer Sciences, University of Glasgow)

  • Laura E. Park

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Mary T. Scott

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Francesca Pellicano

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Andrew Pierce

    (Stem Cell and Leukaemia Proteomics laboratory, University of Manchester
    Manchester Precision Medicine Institute, University of Manchester)

  • Mhairi Copland

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

  • Craig Nourse

    (Institute of Cancer Sciences, University of Glasgow)

  • Sean M. Grimmond

    (University of Melbourne Centre for Cancer Research, University of Melbourne)

  • David Vetrie

    (Institute of Cancer Sciences, University of Glasgow)

  • Anthony D. Whetton

    (Stem Cell and Leukaemia Proteomics laboratory, University of Manchester
    Manchester Precision Medicine Institute, University of Manchester
    Stoller Biomarker Discovery Centre, University of Manchester)

  • Tessa L. Holyoake

    (Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital)

Abstract

Chronic myeloid leukaemia (CML) arises after transformation of a haemopoietic stem cell (HSC) by the protein-tyrosine kinase BCR–ABL. Direct inhibition of BCR–ABL kinase has revolutionized disease management, but fails to eradicate leukaemic stem cells (LSCs), which maintain CML. LSCs are independent of BCR–ABL for survival, providing a rationale for identifying and targeting kinase-independent pathways. Here we show—using proteomics, transcriptomics and network analyses—that in human LSCs, aberrantly expressed proteins, in both imatinib-responder and non-responder patients, are modulated in concert with p53 (also known as TP53) and c-MYC regulation. Perturbation of both p53 and c-MYC, and not BCR–ABL itself, leads to synergistic cell kill, differentiation, and near elimination of transplantable human LSCs in mice, while sparing normal HSCs. This unbiased systems approach targeting connected nodes exemplifies a novel precision medicine strategy providing evidence that LSCs can be eradicated.

Suggested Citation

  • Sheela A. Abraham & Lisa E. M. Hopcroft & Emma Carrick & Mark E. Drotar & Karen Dunn & Andrew J. K. Williamson & Koorosh Korfi & Pablo Baquero & Laura E. Park & Mary T. Scott & Francesca Pellicano & A, 2016. "Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells," Nature, Nature, vol. 534(7607), pages 341-346, June.
    • Handle: RePEc:nat:nature:v:534:y:2016:i:7607:d:10.1038_nature18288
    DOI: 10.1038/nature18288
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    Cited by:

    1. Yinzhe GE & Mang XIAO, 2019. "Chronic Myeloid Leukemia: How to Overcome the Tyrosine Kinase Inhibitors Resistance," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 18(2), pages 13389-13393, May.
    2. Mary T. Scott & Wei Liu & Rebecca Mitchell & Cassie J. Clarke & Ross Kinstrie & Felix Warren & Hassan Almasoudi & Thomas Stevens & Karen Dunn & John Pritchard & Mark E. Drotar & Alison M. Michie & Hea, 2024. "Activating p53 abolishes self-renewal of quiescent leukaemic stem cells in residual CML disease," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Kevin M. Rattigan & Zuzana Brabcova & Daniele Sarnello & Martha M. Zarou & Kiron Roy & Ryan Kwan & Lucie Beauchamp & Amy Dawson & Angela Ianniciello & Ahmed Khalaf & Eric R. Kalkman & Mary T. Scott & , 2023. "Pyruvate anaplerosis is a targetable vulnerability in persistent leukaemic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.

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