Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells
Web of Science
AuthorAbraham, SA; Hopcroft, LEM; Carrick, E; Drotar, ME; Dunn, K; Williamson, AJK; Korfi, K; Baquero, P; Park, LE; Scott, MT; ...
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sGrimmond, Sean
AffiliationCentre for Cancer Research
Document TypeJournal Article
CitationsAbraham, S. A., Hopcroft, L. E. M., Carrick, E., Drotar, M. E., Dunn, K., Williamson, A. J. K., Korfi, K., Baquero, P., Park, L. E., Scott, M. T., Pellicano, F., Pierce, A., Copland, M., Nourse, C., Grimmond, S. M., Vetrie, D., Whetton, A. D. & Holyoake, T. L. (2016). Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells. NATURE, 534 (7607), pp.341-+. https://doi.org/10.1038/nature18288.
Access StatusAccess this item via the Open Access location
Open Access URLPublished version
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.
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