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    The

225

    ;EwingFamilyofTumorsingFamilyotIu

    ;C,ancjFeng’

    ;‘DepatmentofCancer,MianyangCen—

    ;traIHospital,SichuanProvince621000,

    ;China.

    ;DepartmentofCancer.FuzhouHospi

    ;laIofNankingMilitaryDistrict.Fujian

    ;Province350001.China.

    ;0CancerCenterofXinqiaoHospita1.the

    ;ThirdMilitaryUniversity,Chongqing,

    ;400037,China.

    ;Correspondenceto:DonglinWang

    ;Email:a65223682@cta.cq.cn

    ;ThisworkwassupportedbytheNational

    ;NaturaIScienceFoundationofChina.

    ;(No:30100189)

    ;ReceivedFeburary20,2004;accepted

    ;June18,2004.

    ;ChineseJoumalofClinicalOncolgy

    ;Email:COCR@eyou.comTel(Fax):8622-23522919

    ;AB$TRACrThereisevidencefhaf95%offheEwingfamilyoffumors(EF-r) ;haveaEWSFLI1fusiongene.EWSFLI1isatranscriptionfactorwitha ;pivotaIfunctionanditisknownlobindloaspeciaIDNAsequence.Research ;hasdemonstratedlhallheEWSFLI1fusiongeneoccurrenceisrelatedlo ;lheEFT.andithasbeenusedlodiagnose.1realandserveasabasisforEFT ;prognosis.WehavebrieflysummarizedlheprogressoflheEWS-FLI1

    ;fusiongeneinbasicandclinicaIinvestigationwithinthepastseveraIyears. ;KEYWORDS:Ewingfamilyofhsmor,fudongene.SFu1.

    ;SincethereportofthePhiladephiachromosome(PHchromosome)in1960, ;mostofthenewfusiongenes,whichhavebeenidentified, ;arefoundinleukemiaandmalignantlymphoma.Withthedevelopment ;ofmolecularbiology,manyspecifictranslocationsofchromosomes ;havebeenfoundinsolidtumors,especiallyinsofttissuesarcomas

    ;derivedfrommesodermfTable1).[“

    ;TheEwingfamilyoftumors(EFT),whichderivefrom

    ;neuroectoderm,includeclassicEwing’ssarcoma,Askintumorsofthe

    ;chestwall,andperipheralprimitiveneuroectodermaltumorsofboneor ;softtissues.ThefirstcaseofEwingfamilyoftumorswasdescribed

    ;nearly80yearsago.butnowitoccursannuallyintheUSAata ;frequencyof2.7casespermillionchildrenundertheageof15years ;annuallyintheUSA.AlthoughEFTcanOCCt~atanyage,thegreat ;majorityofcasesoccuratlessthan20yearsofage.Approximately95% ;ofEFThaveaspecifictranslocation,t(1l;22)(q24;q12),whichresults ;infusionoftheEWSandFLIlgeneandproductionofanewfusion

    ;proteinEWSFLI1.Experimentsandclinicalcaseshaveshownthat ;EWSFLI1isinvolvedintumorigenesisandprogressionofEFT,andit ;hasbecomeusedfordiagnosis,treatmentandabasisofprognosis.H-7] ;oftheEWSFU1fusiongene

    ;Thespecifict(11;22)(q24;q12)chromosomaltranslocationoccurring ;in95%ofEFTiscausedbyrearrangementofthe5’halfoftheEWS

    ;geneonchromosome22q12withthe3’halfoftheFLI1geneon

    ;

    ;226ChineseIournalofClinicalOncology2004/Volume1/Number3 ;Table1.Partiallistofthechromosometranslocationsandfusiongenesinsoft-tissuesarcomas

    ;PNET:primitiveneuroectodermaltumor;NK:notknown;RMS:rhabdomyosarcoma ;chromosomel1q24.IllThe5’halfoftheEWSgene

    ;containsatransformationdomainwhichcontainsan

    ;abundanceofglutamineandthe3’halfoftheEWSgene

    ;includesaTATA-bindingprotein(TBP)codetypicalof ;aRNAbindingfactor.EWSisafunctional

    ;RNAbindingproteinthat,alongwithTLSandanovel

    ;TATAbindingproteinassociatedfactor,TAFII68

    ;(alsoknownasRBP56),formsanewfamilyofrelated

    ;proteins.BothTLSandEWScanfunctionas

    ;TATAbindingproteinassociatedfactors(TAFIIs).[41

    ;ThissuggeststhatEWSmaymediatethestepsof

    ;nascenttranscriptswiththebasaltranscription

    ;apparatus.However,theEWSportionofEWSFLIl

    ;mayberedirectedtootherproteintargetsbecauseof

    ;chromosomalconformationchangesinducedbythe

    ;genefusion.[81FLIlisamemberoftheETS

    ;(erythroblastosisvirusassociatedtransforming

    ;sequences)familyoftranscriptionfactorswhichcan ;activatespecifictargetgenesbybindingtotheircognate ;DNAsequencesthroughtheirDNAbindingregions.

    ;RecentresearchhasshownthatFLIlhasaclose

    ;relationshiptocellimmortalizationresultingincancer. ;StudiesalsohaveshownthatFLIlhasarelationto

    ;vascularizationandgrowthofneuroectoderm.The5’

    ;halfoftheFLIlgenecontainsatransformationdomain

    ;andthe3’halfoftheFLI—lgeneisaDNAbinding

    ;domain(DBD).TheETSfamilymembersaredefined

;bythepresenceofahighlyconserved85aminoacid

    ;domainnamedtheETSdomain.Theconserveddomain ;isthemainpartoftheDBDintheETSfamily. ;ComputeranalysisshowsthattheNterminalofthe

    ;ETSdomainhasaahelicalstructureandthe ;Cterminalhasaconservedstructure.TheDNA ;sequenceboundbyETScontainsapurinerich

    ;sequencecenteredaroundaconservedGGAA,1

    ;polynucleotideandisnotthesameindifierentmembers ;oftheETSfamily.9IntheEWSFLIlfusionprotein.

    ;theRNAbindingmotifcontainingtheCterminalhalf

    ;OfEWSisreplacedbytheDBDoftheFLIlprotein.

    ;TheEWSFLIlisformedbythetransformation

    ;domainofEWSandDBDofFLI1.Itisbelievedthat

    ;theEWSFLIlisanewtransformationfactor.which ;canrecognizeaspecialdomainupstreamfi-omthegene ;andcanactivatethetransformation.IntheEWSFLIl

    ;fusionprotein.boththeNterminaldomainofEWSand

    ;theDBDofFLIlarenecessaryforthetransforming ;activity.Researchhasindicatedthattheactivationof ;transformationbytheEWSFLIlismuchstrongerthan

    ;thatoftheFLIlinnormalcells.anditevencan

    ;transfcIrillculturedNIH3T3cells.I10]Toensurethatthe ;DBDdomaininthe3’endofFLI—linEwing’ssarcoma

    ;canrecognizeandbindwithaspecialgenesequence, ;Maoeta1.ll1testedthebindingactivityof22different ;genesequencesandfoundthatACCGGAAGTwasthe ;best.

    ;Ithasbeendemonstratedinclinicalstudies.that ;variousEFTshavedifierentclinicalbehaviors, ;progressionandtherapeuticefficacies.These ;characteristicshaveacloserelationtothedifferent ;fusiontypesthatarecausedbyvariationsi11the ;

    ;locationsoftheEWSandFLIlgenomicbreakpoints.

    ;Meloteta1.?reportedthatatleastl2typesof

    ;EWSFLIlchimerictranscriptshadbeenobservedin ;clinicalinvestigations.andthefusionofEWSexon7to ;FU1exon6(type1)orFLI1exon5(type2)accounted

    ;forabout60%and25%ofEWSFLIlfusions

    ;respectively.Thedifferentfusiontypeshaveno ;significantdifferenceinbiologicalactivityandthe ;fusionoftheNterminaldomainofEWS.encodedby

    ;exonsl7,withDBDofFLI1,encodedbyexon9,are

    ;theminimalcomponentsneedforactivety.The ;differenceinclinicalbehavior,progressionand ;therapeuticefficacyforEFTisduetothecomponentsof ;EWSandFLI1.Theclinicalbehaviorandtherapeutic ;efficacyoffusiontype1isfoundintumorsless ;malignant.In1999,Lineta1.【圳usedanelectrophoretic

    ;mobilityshiftassay(EMSA)todetecttheradioactivity ;oftheisotopelabeledDNA.containingthe

    ;ACCGGAAGTsequence.in7difierentEWSFLIl

    ;fusiontypesofEFTandfoundthattheywerealmostthe ;same.TheyalsoconstructedareporterplasmidpS2by ;ligatingtheACCGGAAGTsequenceintotheSacIand ;KpnIsitesofpGL3Promoter(Promega).Tocompare

    ;theratioofluciferaseactivity.thepS2wastransferred ;usingliposomesinto7differentEwing’ssarcomacells

    ;andcontrolcellsfHelaandNIH3T3).Theresults ;showedthattheratioofluciferaseactivityinthe ;Ewing’ssarcomacellswasmuchhigherthanthatin

    ;conffolcellsfP=0.003)andthattheACCGGAAGT ;wasthebestbindingsequenceofEWSFLI1.

    ;ClinicaI

    ;gene

    ;Itisobviousthatthemoleculardiagnosisofcancer ;dependsonspecialmolecularmarkers.Becausespecial ;molecularmarkersusedfordiagnosisarefew,the ;clinicalapplicationofmoleculardiagnosisislimited. ;Fusiongenesoftumorscausedbyspecialchromosomal ;translocationsarehighlyspecificandhaveapotentialof ;becomingatoolformoleculardiagnosis,histological ;typingandjudgingtherapeuticefficacy,reoccurrence ;andprognosis.[131Clinicalresearchesarenowfocusing ;onhowtousetheEWS..FLI..1fusiongenetodetermine ;EWS-FLI-1fusiongene/GangFengeta1.227

    ;theoptimalEFTtherapy.

    ;Clinicianshavedifficultyindiagnosis,treatmentand ;prognosisofEFT,becausethehistologicaland ;immunohistochemicaldifferencesarefewbetweenEFT ;andthesmallblueroundcelltumors(SBRCP).We ;knowthat95%ofEFThaveaspecificchromosome ;translocation,(11;22)(q24;q12),andthatthefusionof ;EWSandFLI1leadstohighexpressionofFLI1.To

    ;evaluatetheexpressionofFLI1in132SBRCP

    ;determinedbypathology.Folpeeta1.[14]usedantiFLI1

    ;polyclonalantibodyandimmunohistochemical

;technology.TheyfoundthattheexpressionofFLI1

    ;wasseenin29of41(71%)ES/PNET,7of8(88%) ;lymphoblasticlymphomas,1ofasingle(100%) ;desmoplasticroundcelltumorfithastheEWSFLI1

    ;gene),0of8poorlydifferentiatedsynovialsarcomas ;(PDSS),0of32rhabdomyosarcomas(RMS),0of30 ;neuroblastomas(NB),0of8esthesioneuroblastomas ;(ENB),0of3Wilms’tumorsand0ofasingle

    ;mesenchymalchondrosarcoma.Theirresearch ;demonstratedthatimmunohistochemistrycould ;distinguishEFTfromSBRCP.

    ;AtonetimeantibodiesforCD99weresuggestedasa ;specificmarkerforEFT.butnowweknowthatitiSnot ;specific.TheexpressionofCD99isonthecell ;membranebutEWSFLI1isinthenucleus.Specificity ;foranuclearmarkerisgreaterthanoneonthecell ;membrane.Forexample.NBandENBtumorsare ;positivewhentestedbyFLIlantibodybuttheyare

    ;almostalwaysnegativewhentestedbyCD99antibody. ;TheexpressionofFLI1isalsohelpfulindistinguishing ;EFTfromothertumorsthatmaybeCD99positive,

    ;suchasPDSS.

    ;Inrecentyears,autologousbonemarrow

    ;transplantationhasbeenusedtotreatEFT.Toavoid ;reimplantationofthetumorcellsandEFT

    ;reoccurrence,onemustmakesurethatnotumorcells ;remaininthegraft.Traditionaltechnologyhasbeen ;usedtodetecttheexistenceoftheEFTcells,butthe ;sensltl’Vl’tyisnothigh.around1%.UsingRT—PCR

    ;technology.Vichaeta1.7foundtheEWSFLI1fusion

    ;genetobenegativein31bonemarrowsamplesand5 ;bloodsamples,and7differentfusiontypeswerefound ;in7autologousbonemarrowtransplantations.This ;

    ;228ChineseJournalofClinicalOncology2004/Volume1/Number3

    ;researchsuggeststhatRTPCRismoresensitivethan

    ;histologyindetectingtheexistenceofEFTcells,anda ;moreimportantassayinconductingautologousbone ;marrowtransplantations.

    ;TheEWSFLIlfusiongeneisfoundin95%ofEFT

    ;andthisfusiongeneisfundamentalfortheoccurrence ;anddevelopmentofEFT.EWSFLIlisatranscription

    ;factorthathasapotentactivitybybindingwitha ;specialDNAsequencewhichleadstoahighexpression

;ofitselfandthedownstreamgenes.TheEWSFLIl

    ;hasalreadybeenusedinthediagnosis.treatmentand ;prognosisofEFT,andisbecomingatargetforgene ;therapy.Genefusionisverycommonincancer.The ;importantgoalnowishowtoutilizetheknowledge ;abouttheEWSFLI.1fusiongeneinrelationtoEFTas ;wellastoothertumors.

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    ;cal[标签:快照]

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