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 Whetton, Tessa L. Holyoake

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    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.

    Original languageEnglish
    Pages (from-to)341-346
    Number of pages6
    JournalNature
    Volume534
    Issue number7607
    Early online date8 Jun 2016
    DOIs
    Publication statusPublished - 16 Jun 2016

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