骨髓增生异常综合征PPT课件

.,骨髓增生异常综合征（Myelodysplasticsyndromes,MDS）,.,2,.,3,一组起源于造血干细胞(HSC)的异质性的克隆性疾病,以外周血一系或多系减少骨髓增生正常或亢进伴病态造血和高风险向急性白血病转化为特征。Agroupofclonalneoplasms;heterogeneous;Hematopoieticstemcells(HSC)orprogenitors;CytopeniaMyelodysplasia;ineffectivehematopoiesisIncreasedriskofblastictransformation:-preleukemia,smoulderingleukemia,定义,.,MDSvsAML,Blood.2013;121:3811,.,5,发病情况,发病年龄：成人发病为主，老年更多见，轻微男性发病优势发病率：美国报告为2-12/10万；70岁以上者50/10万(IntJHematol2001,73:405),.,6,高龄，外因；原发性、继发性MDS：tMDS（烷化剂、表鬼臼毒素类）先天/家族性MDSHSC增生失控、分化受阻、细胞凋亡增加细胞遗传学异常：-5/5q-，-7/7q-基因水平的改变；AML1-MDS1-EVI1融合基因表观遗传学调控异常,病因、发病机理,.,7,分类,FAB:1976;1982中国1986WHO:2000;2008;2016,.,8,FAB1976,DysmyelopoieticsyndromesRARAEB,BrJHaematol1976,33:451,.,9,MDS(FAB1982),.,10,FABWHO2000,与AML界限：骨髓原始细胞降为20%RAEB-t归入AML；但有t(8;21)、t(15;17)、inv(16)/t(16;16)等核型异常者即使小于20%也应诊断为白血病CMML:MDS/MPD,.,WHO2000,.,12,WHO20002008,增加RN、RT，与RA一起组成RCUD;重新定义MDS-U（不再包括RN和RT）增加ChildhoodMDS（RCC）RCMD与RCMD-RS合并t-MDS/t-AML不再区分原因（烷化剂or鬼臼毒素类）,.,WHO2008,.,14,WHO2016,MDSwithsinglelineagedysplasia(MDS-SLD)MDSwithmultilineagedysplasia(MDS-MLD)MDSwithringsideroblasts(MDS-RS)MDS-RSandsinglelineagedysplasia(MDS-RSSLD)MDS-RSandmultilineagedysplasia(MDS-RSMLD)MDSwithexcessblasts(MDS-EB1,MDS-EB2)MDSwithisolateddel(5q)(5q-syndrome)MDS,unclassifiable(MDS-U)Provisionalentity:Refractorycytopeniaofchildhood(RCC),.,15,.,16,CHIPDyserythropoiesis;Dysgranulopoiesis;DysmegakaryopoiesisTrephinebiopsy:Cellularity;Myelofibrosis(reticulin,MDSwithfibrosis);Reportestimated%ofCD34+blasts;Dysmegakaryopoiesis(CD61);ALIP(abnormallocalizedimmatureprecursors),.,24,红系病态造血,Normal,Ringedsideroblasts,.,25,粒系病态造血,.,26,巨核系病态造血,.,27,诊断、鉴别诊断,PB：cytopenia(s)BMsmear：dysplasiaBMbiopsy：ALIPFlowcytometryCytogenetic：5q-/-5,-7Molecular：NGSMA,AA,PNH,MPN,AML,.,28,.,29,MinimalDiagnosticCriteriainMDS,PrerequisitecriteriaConstantcytopeniainoneormoreofthefollowingcelllineages:erythroid(hemoglobulin15%ringedsideroblasts5-19%BlastcellsinbonemarrowsmearsTypicalchromosomalabnormality:conventionalkaryotypingorFISH,ValentP,etal.LeukemiaResearch2007:727-736,.,30,MinimalDiagnosticCriteriainMDSContd.,(C)Co-criteria(forpatientsfulfillingAbutnotB”):Typicalclinicalfeatures,macrocytictransfusion-dependentanemia.典型临床特征，输血依赖大细胞贫血AbnormalphenotypeofBMcellsindicativeofamonoclonalpopulationdeterminedbyflowcytometry单克隆表型-流式Molecular:MonoclonalcellpopulationinHUMARAassay,genechipprofiling,orpointmutationanalysis(e.g.RASmutations)单克隆表型-基因异常Markedlyandpersistentlyreducedcolony-formationofBMor/andcirculatingprogenitorcells(CFU-assay)骨髓集落培养减低,ValentP,etal.LeukemiaResearch2007:727-736,.,31,MDS治疗原则,治疗方案设计要求个体化、分层personalizationstratification;支持、对症治疗仍是主要措施（Bestsupportivecare)：红细胞、血小板输注，CSFs,EPO抗感染去铁治疗FDA批准的药物（3个）：去甲基化药物:-阿扎胞苷（5-azacytidine2004）-地西他滨（decitabine,2006;中国2009）来那度胺（lenalidomide，2005）：del(5q)首选造血干细胞移植,.,32,HypomethylatingCytosineAnalogues,地西他宾FDA2006,阿扎胞苷FDA2004,.,33,地西他滨（Decitabine，Dacogen),15-30mg/m2(10-50mg)intravenouslydaily3-5days/cycle.,.,34,DecitabinePharmacologyMechanismofAction,DecitabineisanS-phasespecificagentAntineoplasticactivityattributedtoInhibitionofcellproliferationathigherdosesincorporationintoDNAblockingofDNAsynthesiscytotoxicitynonreversiblecovalentlinkingwithDNAmethyltransferaseInductionofhypomethylationatlowerdosespromotingcelldifferentiationre-expressionoftumorsuppressorgenesstimulationofimmunemechanismssuppressionoftumorgrowth,.,35,HypomethylatorsvsIntensiveChemoRxinMDSwith10-30%Blasts,330pts:93(28%)RxwithHMAand237(72%)withchemoRxMVA:worsesurvivalwithchemoRx,Nazha.Blood122:abst2788:2013,.,36,来那度胺(Lenalidomide,瑞复美),AntiangiogenicImmunomodulatoryimidedrugs(IMiDs)5q-syndrome10mg/dayorallyMultiplemyeloma,.,37,Thalidomide（沙利度胺、反应停）,developedbyGermanpharmaceuticalcompanyGrnenthalsoldfrom1957to1961topregnantwomen,asanantiemetictocombatmorningsicknessandasanaidtohelpthemsleepapproximately10,000childrenwerebornwithseveremalformities,includingphocomelia（SealBaby)1991Dr.GillaKaplanatRockefellerUniversityshowedthatthalidomideworkedinleprosybyinhibitingtumornecrosisfactoralpha,.,38,其它治疗选择,免疫抑制剂：ATG,CsA,Dexamethasone小剂量化疗：Low-dosecytarabine；DA亚砷酸ATRAAmifostine阿米福汀(氨磷汀)Clinicaltrials,.,39,预后,.,40,.,41,Prognosticmodels,IPSSIPSS-RWPSSOthers:GlobalMDACCmodel;MDACClowerriskmodel;Impactofcomorbidities,.,发病机制及分子治疗,细胞遗传学异常分子遗传学（基因结构）异常表观遗传学调控紊乱,.,43,Nybakken16:145-158,CytogeneticfindingsinMDS,.,44,.,45,DistributionofrecurrentmutationsandkaryotypicabnormalitiesinMDS,.,46,MutationallandscapeinMDS,Haferlachetal.Leukemia2013,Targetedsequencingofalimitednumberofgenescandetectmutationsin80%to90%ofMDSpatients;themostcommonlymutatedgenesinMDSareSF3B1,TET2,SRSF2,ASXL1,DNMT3A,RUNX1,U2AF1,TP53,andEZH2,.,47,MutationsofTP53&SF3B1,TP53mutationisassociatedwithaggressivediseaseinMDSingeneralandappearstopredictpoorerresponsetolenalidomideinpatientswithdel(5q).WithregardtoMDSwithringsideroblasts(MDS-RS),recurrentmutationsinthespliceosomegeneSF3B1arefrequentinMDSandareassociatedwiththepresenceofringsideroblasts.So,ifanSF3B1mutationisidentified,adiagnosisofMDS-RSmaybemadeifringsideroblastscompriseasfewas5%ofnucleatederythroidcells,.,48,Impactofmutationofp53orDNMT3AonsurvivalofMDSptsw/HSC,.,49,表观遗传学调控异常epigenetics,不涉及基因一级结构改变的表达调控机制，即基因DNA序列不发生改变的情况下，基因的表达水平与功能发生改变，并产生可遗传的表型三大特征：DNA序列本身不变、可遗传、可逆性RegulationoftranscriptionDNAmethylation甲基化Histonemodifications组蛋白修饰ChromatinremodelingPseudogenesRegulationofpost-transcriptionNon-codingRNA：microRNA,siRNA,lncRNARiboswitch,.,50,DNA甲基化的基本作用：抑制基因表达,.,51,DNA+histones=Nucleosome（转录单位）Acetylation/deacetylation乙酰化-去乙酰化Methylation/demethylation甲基化-去甲基化Phosphorylation/dephosphorylation磷酸化状态,组蛋白修饰Histonemodifications“histonecode”,.,52,EpigeneticAlterations,m,m,m,m,methylation,acetylation,phospho