Epigenetic reprogramming sensitizes CML stem cells to combined EZH2 and tyrosine kinase inhibition

Scott, M. T. et al. (2016) Epigenetic reprogramming sensitizes CML stem cells to combined EZH2 and tyrosine kinase inhibition. Cancer Discovery, 6(11), pp. 1248-1257. (doi:10.1158/2159-8290.CD-16-0263) (PMID:27630125)

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Abstract

A major obstacle to curing chronic myeloid leukaemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)-persistent leukemic stem cells (LSCs). These are BCR-ABL1 kinase-independent (1, 2), refractory to apoptosis (3, 4) and serve as a reservoir to drive relapse or TKI-resistance. We demonstrate that Polycomb Repressive Complex 2 (PRC2) is mis-regulated in chronic phase (CP) CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell (HSC) survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant up-regulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in CML patients receiving TKIs.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Saffrey, Dr Peter and Sinclair, Miss Amy and Scott, Dr Mary and Pellicano, Dr Francesca and Kinstrie, Dr Ross and Holyoake, Professor Tessa and Dunn, Mrs Karen and Crossan, Dr Andrew and Vetrie, Professor David and Korfi, Mr Koorosh and Jorgensen, Dr Heather and Hopcroft, Dr Lisa and Cassels, Miss Jennifer
Authors: Scott, M. T., Korfi, K., Saffrey, P., Hopcroft, L. E.M., Kinstrie, R., Pellicano, F., Guenther, C., Gallipoli, P., Cruz, M., Dunn, K., Jorgensen, H. G., Cassels, J. E., Hamilon, A., Crossan, A., Sinclair, A., Holyoake, T. L., and Vetrie, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cancer Discovery
Publisher:American Association for Cancer Research
ISSN:2159-8274
ISSN (Online):2159-8290
Published Online:14 September 2016
Copyright Holders:Copyright © 2016 American Association for Cancer Research
First Published:First published in Cancer Discovery 2016
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
469161The Histone code of human haematopoietic stem cell developmentDavid VetrieWellcome Trust (WELLCOME)GR083755RI CANCER SCIENCES
498551Key survival pathways in chronic myeloid leukaemia (cml) stem cells and novel approaches to their eradicationTessa HolyoakeCancer Research UK (CAN-RES-UK)11008RI CANCER SCIENCES
439231Is Bcr-Able expression relevant for the survival of cancer stem cells in chronic myeloid leukaemiaTessa HolyoakeMedical Research Council (MRC)G0600782RI CANCER SCIENCES
540351The relevance of autocrine growth factor activation to the survival and proliferation of primitive chronic myeloid leukaemia (CML) cells.Paolo GallipoliMedical Research Council (MRC)G1000288RI CANCER SCIENCES
500231BBSRC Doctoral Training Grant 2009-15Katherine WestBiotechnology and Biological Sciences Research Council (BBSRC)BB/F016050/1RI CANCER SCIENCES
542691Development of a flow cytometry service within the Paul O'Gorman Leukaemia Research CentreAlison MichieThe Kay Kendall Leukaemia Fund (KENDALL)KKL501RI CANCER SCIENCES