肿瘤学细胞分化课件

CellDifferentiation&Cancer肿瘤学细胞分化细胞分化（differentiation）是指同源细胞逐渐发育成具备稳定形态结构、生理功能和生化特征的另一类型细胞的过程。细胞分化过程是由一系列基因产物（regulatoryproteins）调控的。

i.e.,每个基因的表达都必须：在正确的细胞中；在正确的时间；对正确的信号产生正确的反应；产生正确的表达水平。肿瘤学细胞分化例子：眼形成的关键调控蛋白Ey（果蝇）ey

基因早期细胞（发育成腿）腿中眼细胞分化眼形成肿瘤学细胞分化InductionofPluripotentStemCellsfromAdultHumanFibroblastsbyDefinedFactorsCell2007,131,861-872（Oct3/4,Sox2,Klf4,c-Myc

）肿瘤学细胞分化肿瘤学细胞分化LeukemiaAcuteChronicLymphoidMyeloidLymphoidMyeloid(CLL)(CML)(ALL)AMLM0M1M2M3M4M5M6M7FAB:肿瘤学细胞分化

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

(APL)肿瘤学细胞分化1988:Breakthroughintreatment

fromChina肿瘤学细胞分化1990:MultiplegroupsidentifyRARaast(15;17)breakpoint肿瘤学细胞分化AcutePromyelocyticLeukemiaSTAT5b(17q21)Blood93,3167(1999)肿瘤学细胞分化Howdoyoutestifafusionproteinisoncogenic?+PNAS96,15103(1999)肿瘤学细胞分化HowdoesPML-RARainducesAPL?

HowdoesATRAinduceremission?肿瘤学细胞分化LossofactivationdomainCoiled-coildomainallowsdimerization肿瘤学细胞分化CorepressorCoactivatorRARRXR肿瘤学细胞分化Jepsen,K.etal.JCellSci2002;115:689-698Transcriptionalrepressionbynuclearreceptorsisregulatedbyrecruitmentoftheco-repressorsN-CoRand/orSMRT肿瘤学细胞分化Atsumi,Aetal

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

LowpenetranceofAPL?肿瘤学细胞分化YES:PU.1+/-miceexpressing

PML-RARahaveahighpenetranceofAPLPNAS102,12513(2005)肿瘤学细胞分化PU.1mutations