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dc.contributor.authorKim, Eunheeen
dc.contributor.authorIlagan, Janine Oen
dc.contributor.authorLiang, Yangen
dc.contributor.authorDaubner, Gerrit Men
dc.contributor.authorLee, Stanley C-Wen
dc.contributor.authorRamakrishnan, Aravinden
dc.contributor.authorLi, Yueen
dc.contributor.authorChung, Young Rocken
dc.contributor.authorMicol, Jean-Baptisteen
dc.contributor.authorMurphy, Michele Een
dc.contributor.authorCho, Hanaen
dc.contributor.authorKim, Min-Kyungen
dc.contributor.authorZebari, Ahmad Sen
dc.contributor.authorAumann, Shlomzionen
dc.contributor.authorPark, Christopher Yen
dc.contributor.authorBuonamici, Silviaen
dc.contributor.authorSmith, Peter Gen
dc.contributor.authorDeeg, H Joachimen
dc.contributor.authorLobry, Camilleen
dc.contributor.authorAifantis, Iannisen
dc.contributor.authorModis, Yorgoen
dc.contributor.authorAllain, Frederic H-Ten
dc.contributor.authorHalene, Stephanieen
dc.contributor.authorBradley, Robert Ken
dc.contributor.authorAbdel-Wahab, Omaren
dc.date.accessioned2016-03-08T16:55:49Z
dc.date.available2016-03-08T16:55:49Z
dc.date.issued2015-05-11en
dc.identifier.citationKim et al. Cancer Cell (2015) Vol. 27, Issue 5, pp. 617–630. doi: 10.1016/j.ccell.2015.04.006en
dc.identifier.issn1535-6108
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/254256
dc.description.abstractMutations affecting spliceosomal proteins are the most common mutations in patients with myelodysplastic syndromes (MDS), but their role in MDS pathogenesis has not been delineated. Here we report that mutations affecting the splicing factor SRSF2 directly impair hematopoietic differentiation in vivo, which is not due to SRSF2 loss of function. By contrast, SRSF2 mutations alter SRSF2’s normal sequence-specific RNA binding activity, thereby altering the recognition of specific exonic splicing enhancer motifs to drive recurrent mis-splicing of key hematopoietic regulators. This includes SRSF2 mutation-dependent splicing of EZH2, which triggers nonsense-mediated decay, which, in turn, results in impaired hematopoietic differentiation. These data provide a mechanistic link between a mutant spliceosomal protein, alterations in the splicing of key regulators, and impaired hematopoiesis.
dc.description.sponsorshipE.K. is supported by the Worldwide Cancer Research Fund. A.R. was supported by the NIH/NHLBI (U01 HL099993), NIH/NIDDK (K08 DK082783), the J.P. McCarthy Foundation, and the Storb Foundation. S.H. and O.A.-W. are supported by grants from the Edward P. Evans Foundation. S.H. was supported by Yale Comprehensive Cancer Center institutional funds. R.K.B. was supported by the Hartwell Innovation Fund, Damon Runyon Cancer Research Foundation (DFS 04-12), Ellison Medical Foundation (AG-NS-1030-13), NIH/NIDDK (R56 DK103854), NIH/NCI recruitment support (P30 CA015704), and Fred Hutchinson Cancer Research Center institutional funds. J.O.I. was supported by an NIH/NCI training grant (T32 CA009657) and NIH/NIDDK pilot study (P30 DK056465). C.L. is supported by a career development award grant from the Leukemia and Lymphoma Society and an ATIP-Avenir grant from the French government. O.A.-W. is supported by an NIH K08 clinical investigator award (1K08CA160647-01), a Department of Defense Postdoctoral Fellow Award in Bone Marrow Failure Research (W81XWH-12-1-0041), the Josie Robertson Investigator Program, and a Damon Runyon Clinical Investigator Award with support from the Evans Foundation. F.H.-T.A. acknowledges support from the NCCR RNA and Disease funded by the Swiss National Science Foundation and the SNF Sinergia CRSII3_127454. Y.L. and Y.M. were supported by NIH/NIGMS grant R01 GM102869 and Senior Research Fellowship Grant 101908/Z/13/Z (to Y.M.) from the Wellcome Trust. J.D. acknowledges assistance from Dr. Nezih Cereb, HistoGenetics (Ossining, NY).
dc.languageEnglishen
dc.language.isoenen
dc.publisherElsevier
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectleukemiaen
dc.subjectmyelodysplastic syndromesen
dc.subjectsplicingen
dc.subjectEZH2en
dc.subjectSRSF2en
dc.subjectSF3B1en
dc.subjectU2AF1en
dc.titleSRSF2 Mutations Contribute to Myelodysplasia by Mutant-Specific Effects on Exon Recognitionen
dc.typeArticle
dc.description.versionThis is the author accepted manuscript. The final version is available from Elsevier via http://dx.doi.org/10.1016/j.ccell.2015.04.006en
prism.endingPage630
prism.publicationDate2015en
prism.publicationNameCancer Cellen
prism.startingPage617
prism.volume27en
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectid101908/Z/13/Z
dcterms.dateAccepted2015-04-10en
rioxxterms.versionofrecord10.1016/j.ccell.2015.04.006en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2015-05-11en
dc.contributor.orcidModis, Yorgo [0000-0002-6084-0429]
dc.identifier.eissn1878-3686
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idNational Institute of General Medical Sciences (NIGMS) (R01GM102869)
pubs.funder-project-idWellcome Trust (101908/Z/13/Z)
rioxxterms.freetoread.startdate2016-05-11


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