Dual targeting of P53 and C-MYC induces selective elimination of leukemic stem cells

Abraham, S. A. et al. (2016) Dual targeting of P53 and C-MYC induces selective elimination of leukemic stem cells. Nature, 534(7607), pp. 341-346. (doi:10.1038/nature18288) (PMID:27281222) (PMCID:PMC4913876)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Abraham, Dr Sheela and Grimmond, Professor Sean and Dunn, Mrs Karen and Carrick, Dr Emma and Vetrie, Dr David and Scott, Dr Mary and Baquero, Dr Pablo and Drotar, Mr Mark and Korfi, Mr Koorosh and Nourse, Dr Craig and Pellicano, Dr Francesca and Holyoake, Professor Tessa and Copland, Professor Mhairi and Hopcroft, Dr Lisa and Miller, Ms Laura
Authors: Abraham, 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., and Holyoake, T. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Nature
Publisher:Nature Publishing Group
ISSN:0028-0836
ISSN (Online):1476-4687
Published Online:08 June 2016
Copyright Holders:Copyright © 2016 Nature Publishing Group
First Published:First published in Nature 534(7607):341-346
Publisher Policy:Reproduced in accordance with the copyright policy of the publisher

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647984CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)C596/A18076RI CANCER SCIENCES
600561MICA: Determining the therapeutic potential of targeting mTORC-1/2 in chronic lymphocytic leukaemia - a pre-clinical studyAlison MichieMedical Research Council (MRC)MR/K014854/1ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C