BET inhibitor resistance emerges from leukaemia stem cells

CY Fong; O Gilan; EYN Lam; AF Rubin; S Ftouni; D Tyler; K Stanley; D Sinha; P Yeh; J Morison; G Giotopoulos; D Lugo; P Jeffrey; SCW Lee; C Carpenter; R Gregory; RG Ramsay; SW Lane; O Abdel-Wahab; T Kouzarides; RW Johnstone; SJ Dawson; BJP Huntly; RK Prinjha; AT Papenfuss; MA Dawson

Journal article

BET inhibitor resistance emerges from leukaemia stem cells

CY Fong, O Gilan, EYN Lam, AF Rubin, S Ftouni, D Tyler, K Stanley, D Sinha, P Yeh, J Morison, G Giotopoulos, D Lugo, P Jeffrey, SCW Lee, C Carpenter, R Gregory, RG Ramsay, SW Lane, O Abdel-Wahab, T Kouzarides Show all

Nature | Published : 2015

DOI: 10.1038/nature14888

Abstract

Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistan..

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University of Melbourne Researchers

Enid Lam Author

Alan Rubin Author

Rob Ramsay Author

Ricky Johnstone Author

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Grants

Awarded by National Cancer Institute

Funding Acknowledgements

We thank A. Bannister for critical reading of the manuscript. The Leukaemia Foundation Australia, Haematology Society of Australia and New Zealand, Royal Australasian College of Physicians and the Victorian Comprehensive Cancer Centre have supported CYF with PhD scholarships. M.A.D. is a Senior Leukaemia Foundation Australia Fellow, VESKI Innovation Fellow and Herman Clinical Fellow. The National Health and Medical Research Council of Australia (1085015; 1066545) and Leukaemia Foundation Australia fund the Dawson laboratory.