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

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, Andrew Pierce, Mhairi Copland, Craig Nourse, Sean M. Grimmond, David Vetrie, Anthony D. Whetton and Tessa L. Holyoake ()
Additional contact information
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
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
Koorosh Korfi: Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital
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
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
Tessa L. Holyoake: Paul O’Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Gartnavel General Hospital

Nature, 2016, vol. 534, issue 7607, 341-346

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature18288

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