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dc.contributor.authorGilan, O
dc.contributor.authorLam, EYN
dc.contributor.authorBecher, I
dc.contributor.authorLugo, D
dc.contributor.authorCannizzaro, E
dc.contributor.authorJoberty, G
dc.contributor.authorWard, A
dc.contributor.authorWiese, M
dc.contributor.authorFong, CY
dc.contributor.authorFtouni, S
dc.contributor.authorTyler, D
dc.contributor.authorStanley, K
dc.contributor.authorMacPherson, L
dc.contributor.authorWeng, C-F
dc.contributor.authorChan, Y-C
dc.contributor.authorGhisi, M
dc.contributor.authorSmil, D
dc.contributor.authorCarpenter, C
dc.contributor.authorBrown, P
dc.contributor.authorGarton, N
dc.contributor.authorBlewitt, ME
dc.contributor.authorBannister, Andrew
dc.contributor.authorKouzarides, Tony
dc.contributor.authorHuntly, Brian
dc.contributor.authorJohnstone, RW
dc.contributor.authorDrewes, G
dc.contributor.authorDawson, S-J
dc.contributor.authorArrowsmith, CH
dc.contributor.authorGrandi, P
dc.contributor.authorPrinjha, RK
dc.contributor.authorDawson, MA
dc.date.accessioned2019-09-27T23:30:21Z
dc.date.available2019-09-27T23:30:21Z
dc.date.issued2016-07
dc.identifier.issn1545-9985
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/297257
dc.description.abstractTargeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis.
dc.languageeng
dc.publisherNature Research
dc.rightsAll rights reserved
dc.subjectStemCellInstitute
dc.titleFunctional interdependence of BRD4 and DOT1L in MLL leukemia.
dc.typeArticle
prism.endingPage681
prism.issueIdentifier7
prism.publicationDate2016
prism.publicationNameNature Structural and Molecular Biology
prism.startingPage673
prism.volume23
dc.identifier.doi10.17863/CAM.44304
dcterms.dateAccepted2016-05-19
rioxxterms.versionofrecord10.1038/nsmb.3249
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2016-07
dc.contributor.orcidBannister, Andrew [0000-0002-6312-4436]
dc.contributor.orcidKouzarides, Tony [0000-0002-8918-4162]
dc.contributor.orcidHuntly, Brian [0000-0003-0312-161X]
dc.identifier.eissn1545-9985
rioxxterms.typeJournal Article/Review
pubs.funder-project-idMedical Research Council (MR/M010392/1)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idEuropean Research Council (647685)
pubs.funder-project-idWorldwide Cancer Research (None)
cam.issuedOnline2016-06-13
rioxxterms.freetoread.startdate2017-01-31


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