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dc.contributor.authorMohr, Sen
dc.contributor.authorDoebele, Cen
dc.contributor.authorComoglio, Fen
dc.contributor.authorBerg, Ten
dc.contributor.authorBeck, Jen
dc.contributor.authorBohnenberger, Hen
dc.contributor.authorAlexe, Gen
dc.contributor.authorCorso, Jen
dc.contributor.authorStröbel, Pen
dc.contributor.authorWachter, Aen
dc.contributor.authorBeissbarth, Ten
dc.contributor.authorSchnütgen, Fen
dc.contributor.authorCremer, Aen
dc.contributor.authorHaetscher, Nen
dc.contributor.authorGöllner, Sen
dc.contributor.authorRouhi, Aen
dc.contributor.authorPalmqvist, Len
dc.contributor.authorRieger, MAen
dc.contributor.authorSchroeder, Ten
dc.contributor.authorBönig, Hen
dc.contributor.authorMüller-Tidow, Cen
dc.contributor.authorKuchenbauer, Fen
dc.contributor.authorSchütz, Een
dc.contributor.authorGreen, Tonyen
dc.contributor.authorUrlaub, Hen
dc.contributor.authorStegmaier, Ken
dc.contributor.authorHumphries, RKen
dc.contributor.authorServe, Hen
dc.contributor.authorOellerich, Thomasen
dc.date.accessioned2017-05-23T10:55:30Z
dc.date.available2017-05-23T10:55:30Z
dc.date.issued2017-04-10en
dc.identifier.issn1535-6108
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/264362
dc.description.abstractThe transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
dc.description.sponsorship.O. and T. Berg (BE 4198/1-1 and BE 4198/2-1) are supported by the Deutsche Forschungsgemeinschaft (DFG). K.S. is supported by a Leukemia and Lymphoma Society Scholar Award and by the National Cancer Institute (R01 CA140292). F.C. is supported by an EMBO long-term fellowship (1305-2015 and Marie Curie ActionsLTFCOFUND2013/GA-2013-609409). F.K. was supported by grants from Deutsche Krebshilfe (grant 109420; Max-Eder program), fellowship 2010/04 by the European Hematology Association, and by the DFG (SFB 1074, project A5). A.R. was supported by the DFG (SFB 1074, project A5) and the gender equality program by the DFG (SFB 1074, project Z2), a fellowship from the Canadian Institutes of Health Research, and the Baustein Startförderung Program of the Medical Faculty, Ulm University. Work in the Department of Haematology in Cambridge is supported by Bloodwise (grant ref. 13003), the Wellcome Trust (grant ref. 104710/Z/14/Z), the Medical Research Council (MC_PC_12009), the Kay Kendall Leukemia Fund (KKL952), the Cambridge NIHR Biomedical Research Center (NF-BR-0412-10321), the Cambridge Experimental Cancer Medicine Centre itself receives funding from NIHR (NF-EC-0412-10442), the Leukemia and Lymphoma Society of America (grant ref. 07037), and core support grants from the Wellcome Trust (100140/Z/12/Z and 097922/Z/11/Z) and MRC (MC_PC_12009).
dc.languageengen
dc.language.isoenen
dc.publisherElsevier (Cell Press)
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectHox genesen
dc.subjectPU.1en
dc.subjectSyken
dc.subjectleukemiaen
dc.subjectmicroRNAen
dc.subjectsignal transductionen
dc.titleHoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling by Suppressing miR-146a in Acute Myeloid Leukemiaen
dc.typeArticle
prism.endingPage562.e11
prism.issueIdentifier4en
prism.publicationDate2017en
prism.publicationNameCancer Cellen
prism.startingPage549
prism.volume31en
dc.identifier.doi10.17863/CAM.9852
dcterms.dateAccepted2017-03-03en
rioxxterms.versionofrecord10.1016/j.ccell.2017.03.001en
rioxxterms.versionVoRen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2017-04-10en
dc.contributor.orcidGreen, Tony [0000-0002-9795-0218]
dc.identifier.eissn1878-3686
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idWellcome Trust (100140/Z/12/Z)
pubs.funder-project-idWellcome Trust (097922/Z/11/Z)
pubs.funder-project-idWELLCOME TRUST (104710/Z/14/Z)
pubs.funder-project-idLeukaemia & Lymphoma Research (13003)
pubs.funder-project-idBlood Cancer UK (07037)
cam.issuedOnline2017-04-10en
cam.orpheus.successThu Jan 30 12:53:47 GMT 2020 - The item has an open VoR version.*
rioxxterms.freetoread.startdate2100-01-01


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International