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dc.contributor.authorGallipoli, Paoloen
dc.contributor.authorGiotopoulos, Georgeen
dc.contributor.authorTzelepis, Konstantinosen
dc.contributor.authorCosta, Ana SHen
dc.contributor.authorVohra, Shabanaen
dc.contributor.authorMedina-Perez, Paulaen
dc.contributor.authorBasheer, Faisalen
dc.contributor.authorMarando, Ludovicaen
dc.contributor.authorDi Lisio, Lorenaen
dc.contributor.authorDias, Joao MLen
dc.contributor.authorYun, Haiyangen
dc.contributor.authorSasca, Danielen
dc.contributor.authorHorton, Sarah Jen
dc.contributor.authorVassiliou, Georgeen
dc.contributor.authorFrezza, Christianen
dc.contributor.authorHuntly, Brianen
dc.date.accessioned2018-05-08T09:53:44Z
dc.date.available2018-05-08T09:53:44Z
dc.date.issued2018-04en
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/275603
dc.description.abstractFLT3 internal tandem duplication (FLT3ITD) are common mutations in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITD AML patients remains poor and demands the identification of novel, specific and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genomewide CRISPR/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and geneexpression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations, and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI, and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITD and other TK activating mutation driven leukemias.
dc.description.sponsorshipP.G. is funded by the Wellcome Trust (109967/Z/15/Z) and was previously supported by the Academy of medical Sciences and Lady Tata Memorial Trust. The Huntly lab is funded by European Research Council, MRC, Bloodwise, the Kay Kendall Leukaemia Fund, the Cambridge NIHR Biomedical Research Centre, and core support grants to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute. C.F. and A.S.H.C are funded by the Medical Research Council, Core Grant to the Cancer Unit. P.M-P. is supported by a grant from Cancer Research UK (C56179/A21617). D.S. is a Postdoctoral Fellow of the Mildred-Scheel Organisation, German Cancer Aid. This research was supported by the CIMR Flow Cytometry Core Facility. We would like to thank the Welcome Trust Sanger Institute facility for the MiSeq run.
dc.format.mediumPrint-Electronicen
dc.languageengen
dc.publisherAmerican Society of Hematology
dc.subjectK562 Cellsen
dc.subjectHumansen
dc.subjectGlutamineen
dc.subjectProtein Kinase Inhibitorsen
dc.subjectEnzyme Activationen
dc.subjectMutationen
dc.subjectfms-Like Tyrosine Kinase 3en
dc.subjectLeukemia, Myeloid, Acuteen
dc.subjectGenome-Wide Association Studyen
dc.subjectCRISPR-Cas Systemsen
dc.subjectTHP-1 Cellsen
dc.titleGlutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.en
dc.typeArticle
prism.endingPage1653
prism.issueIdentifier15en
prism.publicationDate2018en
prism.publicationNameBlooden
prism.startingPage1639
prism.volume131en
dc.identifier.doi10.17863/CAM.22854
dcterms.dateAccepted2018-02-14en
rioxxterms.versionofrecord10.1182/blood-2017-12-820035en
rioxxterms.versionAM*
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2018-04en
dc.contributor.orcidGallipoli, Paolo [0000-0001-7254-2253]
dc.contributor.orcidGiotopoulos, George [0000-0003-1390-6592]
dc.contributor.orcidTzelepis, Konstantinos [0000-0002-4865-7648]
dc.contributor.orcidDias, Joao ML [0000-0002-8451-3537]
dc.contributor.orcidVassiliou, George [0000-0003-4337-8022]
dc.contributor.orcidFrezza, Christian [0000-0002-3293-7397]
dc.contributor.orcidHuntly, Brian [0000-0003-0312-161X]
dc.identifier.eissn1528-0020
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MC_UU_12022/1_do not transfer?)
pubs.funder-project-idMedical Research Council (MR/M010392/1)
pubs.funder-project-idECH2020 EUROPEAN RESEARCH COUNCIL (ERC) (647685)
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)
pubs.funder-project-idMRC (MC_PC_12009)
pubs.funder-project-idWELLCOME TRUST (109967/Z/15/Z)
pubs.funder-project-idMRC (MR/R009708/1)
pubs.funder-project-idCancer Research UK (21617)
pubs.funder-project-idWorldwide Cancer Research (14-1069)
rioxxterms.freetoread.startdate2019-04-12


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