腫瘤學細胞分化課件

CellDifferentiation&Cancer腫瘤學細胞分化細胞分化（differentiation）是指同源細胞逐漸發(fā)育成具備穩(wěn)定形態(tài)結(jié)構(gòu)、生理功能和生化特征的另一類型細胞的過程。細胞分化過程是由一系列基因產(chǎn)物（regulatoryproteins）調(diào)控的。

i.e.,每個基因的表達都必須：在正確的細胞中；在正確的時間；對正確的信號產(chǎn)生正確的反應(yīng)；產(chǎn)生正確的表達水平。腫瘤學細胞分化例子：眼形成的關(guān)鍵調(diào)控蛋白Ey（果蠅）ey

基因早期細胞（發(fā)育成腿）腿中眼細胞分化眼形成腫瘤學細胞分化InductionofPluripotentStemCellsfromAdultHumanFibroblastsbyDefinedFactorsCell2007,131,861-872（Oct3/4,Sox2,Klf4,c-Myc

）腫瘤學細胞分化腫瘤學細胞分化LeukemiaAcuteChronicLymphoidMyeloidLymphoidMyeloid(CLL)(CML)(ALL)AMLM0M1M2M3M4M5M6M7FAB:腫瘤學細胞分化

M2t(8;21)AML1-ETOM1t(9;22)M5t(9;11)M3t(15;17)PML-RARαacutepromyelocyticleukemia“Acutemyelogenousleukemias(AMLs)aregeneticallyheterogeneousandcharacterizedbychromosomalrearrangementsthatproducefusionproteinswithaberranttranscriptionalregulatoryactivities.”MyriamAlcalayet.al.,2003FAB,TranslocationandFusionProteins腫瘤學細胞分化M3t(15;17)PML-RARαacutepromyelocyticleukemia“Acutepromyelocyticleukemia(AMLM3)isnowthemostfrequentlycurableacuteleukaemiainadultsifpromptlydiagnosedandadequatelytreated.”ParmarS,TallmanMS.,2003腫瘤學細胞分化DifferentiationTherapyDifferentiationtherapiesarebroadlydefinedasthosethatinducemalignantreversion(i.e.themalignantphenotypebecomesbenign).Clinically,thesetherapieshavebeenmostsuccessfulforacutepromyelocyticleukemia(APL),withtheuseofall-transretinoicacid(ATRA).Thistreatmenthaschangedacancerwithapreviouslydismaloutcomeintooneofthemosttreatableformsofleukemia.Theexactmechanismsofdifferentiationareunknown—itisunclearifitoccursbyinducingterminaldifferentiation(G0arrest),byinducingdifferentiation‘backwards’tothenon-malignantformofthecell,orbytriggeringapoptosis.ItislikelythatitinvolvesallofthesepathwaysAlexanderISpiraet.Al.,Differentiationtherapy,CurrentOpinioninPharmacology2003腫瘤學細胞分化1949:describedinFranceasaleukemiawithexaggeratedhemorrhagicsymptoms1957Hillestadcoinsitpromyelocyticleukemia1977t(15;17)describedinthreeptsRowleyetalLancet.DrugGeneATRAandacutepromyelocyticleukemia

(APL)腫瘤學細胞分化1988:Breakthroughintreatment

fromChina腫瘤學細胞分化1990:MultiplegroupsidentifyRARaast(15;17)breakpoint腫瘤學細胞分化AcutePromyelocyticLeukemiaSTAT5b(17q21)Blood93,3167(1999)腫瘤學細胞分化Howdoyoutestifafusionproteinisoncogenic?+PNAS96,15103(1999)腫瘤學細胞分化HowdoesPML-RARainducesAPL?

HowdoesATRAinduceremission?腫瘤學細胞分化LossofactivationdomainCoiled-coildomainallowsdimerization腫瘤學細胞分化CorepressorCoactivatorRARRXR腫瘤學細胞分化Jepsen,K.etal.JCellSci2002;115:689-698Transcriptionalrepressionbynuclearreceptorsisregulatedbyrecruitmentoftheco-repressorsN-CoRand/orSMRT腫瘤學細胞分化Atsumi,Aetal

BBRC(2006)345:1475HDAC3RecruitmentAbolishedbyATRAGraphicfromMillipore腫瘤學細胞分化ATRAresolvesthedifferentiationblockint(15;17)acutemyeloidleukemiabyrestoringPU.1expression腫瘤學細胞分化Figure1.ConditionalexpressionofPML-RARAinmyeloidcellssuppressesPU.1.Figure2.LeukemiccellsfromapatientwithAPL(HT93cells)havesuppressedPU.1expression.腫瘤學細胞分化Mueller,B.U.etal.Blood2006;107:3330-3338Figure3.ATRArestoresPU.1expressioninAPLcells腫瘤學細胞分化Mueller,B.U.etal.Blood2006;107:3330-3338Figure4.CEBPfactorsandOCT-1induceactivityoftheproximalPU.1promoterinHT93AAPLcellsfollowingATRAstimulation腫瘤學細胞分化Mueller,B.U.etal.Blood2006;107:3330-3338Figure5.PU.1expressioninprimaryAPLcells:inversecorrelationwithPML-RARAatdiagnosis,andinductionofexpressionfollowingtreatmentwithATRAinvivo腫瘤學細胞分化Copyright?2006AmericanSocietyofHematology.Copyrightrestrictionsmayapply.Mueller,B.U.etal.Blood2006;107:3330-3338Figure6.RestoringPU.1expressioninPML-RARAleukemiccellsinducesgranulocyticdifferentiation腫瘤學細胞分化Mueller,B.U.etal.Blood2006;107:3330-3338Figure7.ReductionofPU.1expressionbysiRNAblocksATRA-induceddifferentiationofHT93AcellsPU.1expression腫瘤學細胞分化hCG-PML-RARaPU.1+/-F1cross(informativeprogeny)Wild-typePU.1+/-hCG-PML-RARahCG-PML-RARa XPU.1+/-DoeslossofonecopyofPU.1contributetoPML-RARadrivenAPL?

LowpenetranceofAPL?腫瘤學細胞分化YES:PU.1+/-miceexpressing

PML-RARahaveahighpenetranceofAPLPNAS102,12513(2005)腫瘤學細胞分化PU.1mutations