Epigenetic dysregulation in chronic myeloid leukaemia: A myriad of mechanisms and therapeutic options

Koschmieder, S. and Vetrie, D. (2018) Epigenetic dysregulation in chronic myeloid leukaemia: A myriad of mechanisms and therapeutic options. Seminars in Cancer Biology, 51, pp. 180-197. (doi:10.1016/j.semcancer.2017.07.006) (PMID:28778403)

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Abstract

The onset of global epigenetic changes in chromatin that drive tumor proliferation and heterogeneity is a hallmark of many forms cancer. Identifying the epigenetic mechanisms that govern these changes and developing therapeutic approaches to modulate them, is a well-established avenue pursued in translational cancer medicine. Chronic myeloid leukemia (CML) arises clonally when a hematopoietic stem cell (HSC) acquires the capacity to produce the constitutively active tyrosine kinase BCR-ABL1 fusion protein which drives tumor development. Treatment with tyrosine kinase inhibitors (TKI) that target BCR-ABL1 has been transformative in CML management but it does not lead to cure in the vast majority of patients. Thus novel therapeutic approaches are required and these must target changes to biological pathways that are aberrant in CML − including those that occur when epigenetic mechanisms are altered. These changes may be due to alterations in DNA or histones, their biochemical modifications and requisite ‘writer’ proteins, or to dysregulation of various types of non-coding RNAs that collectively function as modulators of transcriptional control and DNA integrity. Here, we review the evidence for subverted epigenetic mechanisms in CML and how these impact on a diverse set of biological pathways, on disease progression, prognosis and drug resistance. We will also discuss recent progress towards developing epigenetic therapies that show promise to improve CML patient care and may lead to improved cure rates.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Vetrie, Dr David
Authors: Koschmieder, S., and Vetrie, D.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Seminars in Cancer Biology
Publisher:Elsevier
ISSN:1044-579X
ISSN (Online):1096-3650
Published Online:02 August 2017
Copyright Holders:Copyright © 2017 Elsevier
First Published:First published in Seminars in Cancer Biology 51:180-197
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
679891Targeting p53, cMyc and PRC2 regulatory hubs: A systematic and stratified approach to deliver new therapeutics for CMLTessa HolyoakeBloodwise (BLOODWIS)14033ICS - PAUL O'GORMAN LEUKAEMIA RESEARCH C
681641Crosstalk between PRC2 and BCL6 in regulating CML stem cell survival - from epigenomics to novel therapeutics approachesDavid VetrieBloodwise (BLOODWIS)14047ICS - EPIGENETICS
469161The Histone code of human haematopoietic stem cell developmentDavid VetrieWellcome Trust (WELLCOTR)GR083755RI CANCER SCIENCES
632341MRC Doctoral Training Grant 2013/14, 2014/15 and 2015/16Jeremy MottramMedical Research Council (MRC)MR/K501335/1III - PARASITOLOGY
655501Modulation of H3K27 methylation to eradicate TKI-persistant CML stem cellsDavid VetrieBloodwise (BLOODWIS)14005ICS - EPIGENETICS