dc.contributor.author | Basheer, F | |
dc.contributor.author | Giotopoulos, G | |
dc.contributor.author | Meduri, E | |
dc.contributor.author | Yun, H | |
dc.contributor.author | Mazan, M | |
dc.contributor.author | Sasca, D | |
dc.contributor.author | Gallipoli, P | |
dc.contributor.author | Marando, L | |
dc.contributor.author | Gozdecka, M | |
dc.contributor.author | Asby, R | |
dc.contributor.author | Sheppard, O | |
dc.contributor.author | Dudek, M | |
dc.contributor.author | Bullinger, L | |
dc.contributor.author | Doehner, H | |
dc.contributor.author | Dillon, R | |
dc.contributor.author | Freeman, S | |
dc.contributor.author | Ottmann, O | |
dc.contributor.author | Burnett, M | |
dc.contributor.author | Russell, N | |
dc.contributor.author | Papaemmanuil, E | |
dc.contributor.author | Hills, R | |
dc.contributor.author | Campbell, P | |
dc.contributor.author | Vassiliou, GS | |
dc.contributor.author | Huntly, BJP | |
dc.date.accessioned | 2020-04-22T15:11:01Z | |
dc.date.available | 2019-02-13 | |
dc.date.available | 2020-04-22T15:11:01Z | |
dc.date.issued | 2019-03-19 | |
dc.identifier.citation | Basheer, F., et al. (2019). "Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML." Journal of Experimental Medicine 216(4): 966-981. | en_US |
dc.identifier.issn | 0022-1007 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/63697 | |
dc.description.abstract | Epigenetic regulators, such as EZH2, are frequently mutated in cancer, and loss-of-function EZH2 mutations are common in
myeloid malignancies. We have examined the importance of cellular context for Ezh2 loss during the evolution of acute myeloid
leukemia (AML), where we observed stage-specific and diametrically opposite functions for Ezh2 at the early and late stages
of disease. During disease maintenance, WT Ezh2 exerts an oncogenic function that may be therapeutically targeted. In
contrast, Ezh2 acts as a tumor suppressor during AML induction. Transcriptional analysis explains this apparent paradox,
demonstrating that loss of Ezh2 derepresses different expression programs during disease induction and maintenance.
During disease induction, Ezh2 loss derepresses a subset of bivalent promoters that resolve toward gene activation, inducing a
feto-oncogenic program that includes genes such as Plag1, whose overexpression phenocopies Ezh2 loss to accelerate AML
induction in mouse models. Our data highlight the importance of cellular context and disease phase for the function of Ezh2
and its potential therapeutic implications. | en_US |
dc.description.sponsorship | The Huntly laboratory is funded by CRUK (program C18680/ A25508), the European Research Council (grant 647685 COMAL), the Kay Kendall Leukaemia Fund, the Medical Research Council (MRC), Bloodwise, the Wellcome Trust, and the Cambridge National Institute of Health Research Biomedical Research Centre. F. Basheer is a recipient of a Wellcome Trust PhD for Clinicians award. P. Gallipoli is funded by the Wellcome Trust (109967/Z/15/Z). We acknowledge the Wellcome Trust/ MRC center grant (097922/Z/11/Z) and support from Wellcome Trust strategic award 100140. Research in the laboratory is also supported by core funding from the Wellcome Trust and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. This research was supported by the Cambridge National Institute of Health Research Biomedical Research Centre Cell Phenotyping Hub. | en_US |
dc.format.extent | 966 - 981 | |
dc.language.iso | en | en_US |
dc.publisher | Rockefeller University Press | en_US |
dc.relation.ispartof | JOURNAL OF EXPERIMENTAL MEDICINE | |
dc.rights | CC-BY | |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | acute myeloid leukemia | en_US |
dc.subject | AML | en_US |
dc.subject | Epigenetic regulators | en_US |
dc.subject | EZH2 | en_US |
dc.title | Contrasting requirements during disease evolution identify EZH2 as a therapeutic target in AML | en_US |
dc.type | Article | en_US |
dc.rights.holder | 2019 Basheer et al. | |
dc.identifier.doi | 10.1084/jem.20181276 | |
pubs.author-url | http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000462866300018&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=612ae0d773dcbdba3046f6df545e9f6a | en_US |
pubs.issue | 4 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 216 | en_US |
dcterms.dateAccepted | 2019-02-13 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |