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dc.contributor.authorGallipoli, Paolo
dc.contributor.authorGiotopoulos, George
dc.contributor.authorTzelepis, Konstantinos
dc.contributor.authorCosta, Ana SH
dc.contributor.authorVohra, Shabana
dc.contributor.authorMedina-Perez, Paula
dc.contributor.authorBasheer, Faisal
dc.contributor.authorMarando, Ludovica
dc.contributor.authorDi Lisio, Lorena
dc.contributor.authorDias, Joao ML
dc.contributor.authorYun, Haiyang
dc.contributor.authorSasca, Daniel
dc.contributor.authorHorton, Sarah
dc.contributor.authorVassiliou, George
dc.contributor.authorFrezza, Christian
dc.contributor.authorHuntly, Brian
dc.date.accessioned2018-05-08T09:53:44Z
dc.date.available2018-05-08T09:53:44Z
dc.date.issued2018-04-12
dc.identifier.issn0006-4971
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/275603
dc.description.abstractFLT3 internal tandem duplication (FLT3ITD) mutations are common 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 genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression 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-Electronic
dc.languageeng
dc.publisherAmerican Society of Hematology
dc.subjectK562 Cells
dc.subjectHumans
dc.subjectGlutamine
dc.subjectProtein Kinase Inhibitors
dc.subjectEnzyme Activation
dc.subjectMutation
dc.subjectfms-Like Tyrosine Kinase 3
dc.subjectLeukemia, Myeloid, Acute
dc.subjectGenome-Wide Association Study
dc.subjectCRISPR-Cas Systems
dc.subjectTHP-1 Cells
dc.titleGlutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.
dc.typeArticle
prism.endingPage1653
prism.issueIdentifier15
prism.publicationDate2018
prism.publicationNameBlood
prism.startingPage1639
prism.volume131
dc.identifier.doi10.17863/CAM.22854
dcterms.dateAccepted2018-02-14
rioxxterms.versionofrecord10.1182/blood-2017-12-820035
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2018-04
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.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/Review
pubs.funder-project-idMRC (unknown)
pubs.funder-project-idMedical Research Council (MR/M010392/1)
pubs.funder-project-idEuropean Research Council (647685)
pubs.funder-project-idMedical Research Council (MC_UU_12022/6)
pubs.funder-project-idMedical Research Council (MC_PC_12009)
pubs.funder-project-idWellcome Trust (109967/Z/15/Z)
pubs.funder-project-idMedical Research Council (MR/R009708/1)
pubs.funder-project-idCancer Research UK (21617)
pubs.funder-project-idWorldwide Cancer Research (None)
rioxxterms.freetoread.startdate2019-04-12


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