genetic alterations of m6a regulators predict poorer survival in acute myeloid leukemia 2017 chau-to kwok学术.pdf

该【genetic alterations of m6a regulators predict poorer survival in acute myeloid leukemia 2017 chau-to kwok学术 】是由【探春文档】上传分享，文档一共【6】页，该文档可以免费在线阅读，需要了解更多关于【genetic alterations of m6a regulators predict poorer survival in acute myeloid leukemia 2017 chau-to kwok学术 】的内容，可以使用淘豆网的站内搜索功能，选择自己适合的文档，以下文字是截取该文章内的部分文字，如需要获得完整电子版，请下载此文档到您的设备，方便您编辑和打印。&Oncology(2017)10:-017-0410-6essicalterationsofm6AregulatorspredictpoorersurvivalinacutemyeloidleukemiaChau-ToKwok1,2,3,,3,,3,,2,3*AbstractMethylationofN6adenosine(m6A)isknowntobeimportantfordiversebiologicalprocessesincludinggeneexpressioncontrol,translationofprotein,andmessengerRNA(mRNA),(TCGA)acutemyeloidleukemia(AML)study,wediscoverthatmutationsand/,:RNAmodification,m6A,Leukemia,Acutemyeloidleukemia,TP53mutationTotheeditorcancers,,pel-MethylationofN6adenosine(m6A)isthemostabun-lingreasontodeterminewhethermutations,deletions,dantformofmessengerRNA(mRNA)modificationinandamplificationsofm6Aregulatorygenesareenrichedeukaryotes[1].,proteintranslation,andincludingpatientsurvivalhavenotpreviouslybeensplicinginnormalbiology[1,2].m6Aregulatoryen-“writers”METTL3andMETTL14,Here,wecuratemutations,includingpointmutations,“readers”YTHDF1andYTHDF2,and“erasers”FTOdeepdeletions,andamplificationsofthebestcharacter-andALKBH5[1].m6Aperturbationmediatedviaknock-izedm6Aregulatorygenes,METTL3,METTL14,downorknockoutoftheseenzymescancausecellYTHDF1,YTHDF2,FTO,,decreasedcellproliferation,impairedself-renewalarepossiblyhomozygousdeletionsasmeasuredusingcapacity,anddevelopmentaldefects[1].Forexample,theGenomicIdentificationofSignificantTargetsinablationofMETTL3perturbsembryonicstemcelldif-Canceralgorithm(GISTIC).Fourdistincttypesofferentiation[1].DepletionofFTOandALKBH5leadstohematologicalmalignanciesweresequencedbytheobesityandimpairmentofspermatogenesis,respectivelyCancerGenomeAtlasResearch(work:acute[1].Silencingofm6Amethyltransferasecanresultinmyeloidleukemia(AML),multiplemyeloma(MM),modulationoftheTP53signalingpathwayofrelevanceacutelymphoblasticleukemia(ALL),andchronictotumorigenesis[2].Morerecently,overexpressionoflymphocyticleukemia(CLL),icdatahasbeenFTOhasbeenshowntopromoteleukemogenesis[3].ItmadeavailableviacBioPortal[4].%(5/191)ofAML,%(5/205)ofMM,%(1/106)ofALL,and0%(0/666)ofCLL(Additionalfile1:FigureS1a).ForAML,we*Correspondence:j.******@.aufurtheridentifiedvariationingenecopynumberin1Gene&StemCellTherapyProgram,CentenaryInstitute,UniversityofSydney,Camperdown2050,%(20/191)ofpatients(Additionalfile2:TableS1).2GeneRegulationinCancerLaboratory,CentenaryInstitute,parablefrequencyofcopynumberlossSydney,Camperdown2050,Australiameasuredasshallowdeletion(possiblyheterozygousFulllistofauthorinformationisavailableattheendofthearticle?TheAuthor(s).(/licenses/by//),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedyougiveappropriatecredittotheoriginalauthor(s)andthesource,providealinktomonslicense,(/publicdomain/zero//)appliestothedatamadeavailableinthisarticle,&Oncology(2017)10:39Page2of6deletion)usingGISTIC(n=19)andcopynumbergainOfallclinicopathologicalandmolecularfeaturescon-(n=13)ofm6Aregulatorygenes(Additionalfile1:sideredforthisdenovoAMLcohort[5],olderageFigureS1b).Amongthese,copynumberlossofALKBH5(>60years),whitebloodcellcount>median(15,200peristhemostfrequentinthisAMLcohort(12/191,%).mm3),icrisk,andDNMT3AandNotably,%(9/191)itantTP53mutationsweresignificantlyassociatedwithinfer-copynumbergainorlossofmorethanonem6Aregula-iorOSand/orEFSinunivariateanalyses(Additionalfile5:torygene(Additionalfile2:TableS1).InfouroftheseFigureS3andAdditionalfile6:FigureS4).Wethereforeex-ninecases,acopynumbergainofanm6Awriterwasaminedtheimpactofm6Aregulatorygenemutationsand/itantlywithashallow/eofAMLpatientswithpoorriskanm6Aeraser(Additionalfile2:TableS1),-wereassociatedwithinferiorOSandEFSinpatientsregard-zymesthatmayleadtoincreasedlevelsofRNAm6Alessofage(Additionalfile7:FigureS5).icalter-,FTO,andationsdidnotconferaworseOSorEFSinpatientswithicrisk,whitebloodcellcount>me-mRNAexpressionofthesegenes(Additionalfile3:dian,orDNMT3Amutations(Additionalfile8:FigureS6).FigureS2).CopynumbergainofMETTL14wassig-WefurtherdeterminedthesurvivalofAMLpatientsbinedTP53muta-(Additionalfile3:FigureS2).Thus,(%,Table1)increasedexpressionofm6Aregulatorygenes,≥icalteration(s)ofm6Aregulatorygene(s).WedeterminedwhethermutationsandcopynumberThisgroupofpatientshadworseOSandEFSthanpa-Vs)ofm6Aregulatorygenesareassoci-icalterationsatedwithclinicopathologicalandmolecularfeaturesof(Additionalfile9:FigureS7a).Thereisanon-,METTL14,trendinpatientswithwild-binationYTHDF1,YTHDF2,FTO,icalterationsofm6Aregulatorygenestoex-icAML(P<,Table1).Additionally,weobservedaalterationsofthesegenes(Additionalfile9:FigureS7a).markedincreasedinTP53mutations(P<,Table1)Becausemutations,deletions,amplifications,and/orVsofm6Aregulatorygeneswererelativelyconfined(P<,Table1)ictopatientswithwild-typeFLT3andNPM1(%,-Table1),icalter-logicalandmolecularfeatureswerealsoassociatedwithationsimpactOSandEFSstratifiedbyFLT3orNPM1CNVsofm6Aregulatorygenesalone(Table1).However,-patientswithwild-typeFLT3whohad≥ictorygenesalone(Table1),whichmaybeduetothesmallalteration(s)ofm6Aregulatorygene(s)(P<,numberofcaseswithmutations(n=5).Additionalfile9:FigureS7b).Notably,thesepatientsWefurtherdeterminedwhethershallow/deepdeletionofalsohadworseOS(P<)andEFS(P<)paredtopatientswhohadmutantFLT3butnogen--eticalterationofm6Aregulatorygenes(Additionalfile9:latorygenesoverall,shallow/deepdeletionofALKBH5wasFigureS7b).icalterationsofm6AregulatorygenesicriskandtheasagroupwerealsosignificantlyassociatedwithaworsepresenceofTP53mutationinthisAMLcohort(P<,OSandEFSinpatientswithwild-typeNPM1(P<,Additionalfile4:TableS2).NPM1andFLT3mutationsAdditionalfile9:FigureS7c).IntegrationofmolecularwereabsentinAMLpatientswithshallow/deepdeletionofanalysesofm6Aregulatorygenesmaybeusefultodeter-ALKBH5(Additionalfile4:TableS2).einAMLpatientswhohaveneitherWeperformedKaplan-Meieranalysistoinvestigatethebeenclassifiedas“poorrisk”duetothepresenceofFLT3icalterationsinm6Aregulatorygenesonmutations[6,7]econferredbyNPM1overall(OS)andevent-freesurvival(EFS)inpatientswithmutations[8],particularlywithinagroupofTP53wild-,(P=)andEFS(P<,).InferiorOSandincludesvariablesassociatedwithpoorersurvival,gen-EFSwerealsoevidentinpatientswhohadmutationsand/eticalterationsofm6AregulatorygenesasagroupwereVsofthesegenes()andinthosewithshal-notanindependentprognosticfactorforOS().low/deepdeletionofALKBH5().However,icalterationsofm6AregulatorygenesKwokordingtothemutationand/orcopynumbervariationstatusofgenesencodingm6AregulatoryenzymesOncology&(n=23)No(n=168)PYes(n=18)No(n=168)PYes(n=5)No(n=186)(range)65(18–81)57(21–88)(18–81)57(21–88)65(45–76)(18–88)Sex,no.(%)()87()12()87()4()99()Female7()81()6()81()1()87()%(range)60(30–97)73(30–100)54(30–97)73(30–100)75(33–90)72(30–100)(2017)10:39WBC,×103/(range)(–)(–)(–)(–)(–)(–)icrisk,no.(%)<<(0)37()0(0)37()0(0)37()Intermediate4()105(55)1()105()3()106()Unfavorable19()21(11)17()21()2(1)38()Missingdata0(0)5()0(0)5()0(0)5()Mutation,no./totalno.(%)FLT31/23()53/168()(0)53/168()(20)53/186()()51/168(30)(0)51/168()(20)51/186()()43/168()()43/168()(40)45/186()()34/168()(0)34/168()(20)34/186()(13)20/168()()20/168()(0)23/186()()17/168()(0)17/168()(40)17/186()()15/168()()15/168()(0)16/186()()1/168()<()1/168()<(40)14/186()()10/168()()10/168()(0)12/186()(0)12/168()(0)12/168()(0)12/186()()6/168()()6/168()(0)8/186()()6/168()(20)6/168()(20)6/186(),BMbonemarrow,&Oncology(2017)10:-Meiercurvesforoverallandevent-freesurvivalofTCGAAMLpatientsbythepresenceandabsenceofamutationofm6Aregulatorygenes,bmutationand/V)ofm6Aregulatorygenes,andcdeletion/copynumberlossoftheALKBH5geneencodinganimportantm6A“eraser.”Mutationsincludepointmutation,deepdeletion,-ranktestwasusedtodeterminesignificance.+,-freesurvivalinTCGAAMLpatientsdidindependentlypredictpoorerOS(hazardratio=Identificationofnovelbiomarkersandmoleculartar-;95%CI,–;P=)whenTP53muta-getstoguidethedevelopmentofanti-leukemictherapiestionwasexcludedfromthemodel().Similarre-,thesultswereobservedinmultivariateanalysestopredictmolecularmarkerstodefinesubtypesandprognosisareEFS().Ourresultssupportastrongassociationundercontinuousrefinement[7,9].Giventhatm6Aicalterationsofm6AregulatorygenesandmodificationtoRNAhasbroadphysiologicalfunctions,’esuggeststhatbothandprogressionofdiversecancers,.JournalofHematology&Oncology(2017)10:39Page5of6evolutionofAML[9].icsubgroupsnowin-Additionalfile7:-Meiercurvesforoverallandevent-cludemutationingenesthatencodesplicingregulators,freesurvivalofpatientswithandwithoutmutationand/orcopynumberTP53,icmodifiers[9].V)ofm6Aregulatorygenesby(a)age>60yearsand(b)age<-ranktestwasusedtodeterminesignificance.+,censoredheclinico-data.(PDF405kb)icalter-Additionalfile8:-Meiercurvesforoverallandevent-)ofm6Aregulatorygenesby(A)icTP53riskgroup,(B)whitebloodcellcount(WBC)>medianatdiagnosis,andofthesegenesasagroupandmutations(Table1).(C)-,icalterationsofmAregulatorygenes+,censoreddata.(PDF442kb)einAMLpatients,Additionalfile9:-Meiercurvesforoverallandevent-alt