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) (PMCID:PMC6538532)
|
Text
122894.pdf - Published Version 6MB |
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 Scott, Dr Mary and Kinstrie, Dr Ross and Holyoake, Professor Tessa and Dunn, Mrs Karen and Vetrie, Professor David and Jorgensen, Dr Heather and Sinclair, Miss Amy and Pellicano, Dr Francesca and Crossan, Dr Andrew and Korfi, Mr Koorosh 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 > School 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 |
University Staff: Request a correction | Enlighten Editors: Update this record