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

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • 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
  • Mhairi Copland
  • Craig Nourse
  • Sean M. Grimmond
  • David Vetrie
  • Tessa L. Holyoake


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.

Bibliographical metadata

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

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