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1、Leukemia(2013),1–9&2013MacmillanPublishersLimitedAllrightsreserved0887-6924/13www.nature.com/leuORIGINALARTICLECelloforigindeterminesclinicallyrelevantsubtypesofMLL-rearrangedAML1,2,34,51,2,311,266778AVKrivtsov,MEFigueroa,AUSinha,MCStubbs,ZFeng,PJMValk,RDelwel,KDo¨hner,LBulli
2、nger,ALKung,51,2,3AMMelnickandSAArmstrongMixedlineageleukemia(MLL)-fusionproteinscaninduceacutemyeloidleukemias(AMLs)fromeitherhematopoieticstemcells(HSCs)orgranulocyte–macrophageprogenitors(GMPs),butitremainsunclearwhetherthecelloforigininfluencesthebiologyoftheresultantleuke
3、mia.MLL-AF9-transducedsingleHSCsorGMPscouldbecontinuouslyreplated,butHSC-derivedclonesweremorelikelythanGMP-derivedclonestoinitiateAMLinmice.LeukemiastemcellsderivedfromeitherHSCsorGMPshadasimilarimmunophenotypeconsistentwithamaturingmyeloidcell(LGMP).Geneexpressionanalysesde
4、monstratedthatLGMPinheritedgeneexpressionprogramsfromthecelloforiginincludinghigh-levelEvi-1expressioninHSC-derivedLGMP.ThegeneexpressionsignatureofLGMPderivedfromHSCswasenrichedinpoorprognosishumanMLL-rearrangedAMLinthreeindependentdatasets.Moreover,global50-mClevelswereelev
5、atedinHSC-derivedleukemiasascomparedwithGMP-derivedleukemias.Thismirroredadifferenceseenin50-mCbetweenMLL-rearrangedhumanleukemiasthatareeitherEVI1positiveorEVI1negative.Finally,HSC-derivedleukemiasweremoreresistanttochemotherapythanGMP-derivedleukemias.Thesedatademonstrateth
6、atthecelloforigininfluencesthegeneexpressionprofile,theepigeneticstateandthedrugresponseinAML,andthatthesedifferencescanaccountforclinicalheterogeneitywithinamolecularlydefinedgroupofleukemias.Leukemiaadvanceonlinepublication,11January2013;doi:10.1038/leu.2012.363Keywords:MLL;ce
7、lloforigin;geneexpression;DNAmethylation;chemotherapy;drugresistanceINTRODUCTIONunderlyingbiologicaldifferencesinacytogeneticallyAcutemyeloidleukemia(AML)isahematopoieticdisorderthathomogenousgroupofAMLmaymeritreadjustmentofresultsinaccumulationofabnormalimmaturemyeloidcellsi
8、nthetherapeuticsortreatmentforindividualpatientsbasedonbonemarrow(BM
