骨髓增生异常综合征.pptx

骨髓增生异常综合骨髓增生异常综合征征（Myelodysplastic syndromes,MDS）骨髓增生异常综合征第1页2骨髓增生异常综合征第2页一组起源于造血干细胞(HSC)异质性克隆性疾病,以外周血一系或多系降低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。A group of clonal neoplasms;heterogeneous;Hematopoietic stem cells(HSC)or progenitors;CytopeniaMyelodysplasia;ineffective hematopoiesisIncreased risk of blastic transformation:-preleukemia,smouldering leukemia定义定义3骨髓增生异常综合征第3页MDS vs AMLBlood.;121:3811骨髓增生异常综合征第4页发病情况发病情况发病年纪：成人发病为主，老年更多见，轻微男性发病优势发病率：美国汇报为2-12/10万；70岁以上者50/10万(Int J Hematol,73:405)5骨髓增生异常综合征第5页高龄，外因；高龄，外因；原发性、继发性原发性、继发性MDS：tMDS（烷化剂、表鬼臼毒素类）（烷化剂、表鬼臼毒素类）先天先天/家族性家族性MDSHSC增生失控、分化受阻、细胞凋亡增加增生失控、分化受阻、细胞凋亡增加细胞遗传学异常：细胞遗传学异常：-5/5q-，-7/7q-基因水平改变；基因水平改变；AML1-MDS1-EVI1融合基因融合基因表观遗传学调控异常表观遗传学调控异常病因、发病机理MDSMPNLeukemiaProliferationDifferentiation Apoptosis6骨髓增生异常综合征第6页分类分类FAB:1976;1982 中国1986WHO:;7骨髓增生异常综合征第7页FAB 1976Dysmyelopoietic syndromesRARAEBBr J Haematol 1976,33:4518骨髓增生异常综合征第8页MDS(FAB 1982)MDS(FAB 1982)%Ringed SideroblastsPB BlastsBM BlastsPB MonocytesRA 1%15%1%5%RAEB 5%21-30%CMML 1x109/L9骨髓增生异常综合征第9页FABWHO l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%也应诊疗为白血病lCMML:MDS/MPD10骨髓增生异常综合征第10页WHO PB blastsBM blasts 1RA5%5%low risk2RARSRS15%3RCMD4RCMD-RSRS15%5Del(5q)6RAEB-1 10%in one single cell line*or 10%with recurrent abnormal cytogenetics Cytopenia(6 month),Transfusion-dependent,macrocytic anemia Hgb 10g/dL ANC 1.5 x 109/L PLT 50%MDS with hypocellular marrow MDS with fibrosisMDS with thrombocytosisPNHMPNAAMDSAML28骨髓增生异常综合征第28页Minimal Diagnostic Criteria in MDS(A)Prerequisite criteriaConstant cytopenia in one or more of the following cell lineages:erythroid(hemoglobulin 11 g dL-1);or neutrophilic(ANC1500-1);or megakaryocytic(platelets 15%ringed sideroblasts5-19%Blast cells in bone marrow smearsTypical chromosomal abnormality:conventional karyotyping or FISHValent P,et al.Leukemia Research:727-73629骨髓增生异常综合征第29页Minimal Diagnostic Criteria in MDS Contd.(C)Co-criteria(for patients fulfilling A but not B”):Typical clinical features,macrocytic transfusion-dependent anemia.经典临床特征，输血依赖大细胞贫血Abnormal phenotype of BM cells indicative of a monoclonal population determined by flow cytometry 单克隆表型-流式Molecular:Monoclonal cell population in HUMARA assay,gene chip profiling,or point mutation analysis(e.g.RAS mutations)单克隆表型-基因异常Markedly and persistently reduced colony-formation of BM or/and circulating progenitor cells(CFU-assay)骨髓集落培养减低Valent P,et al.Leukemia Research:727-73630骨髓增生异常综合征第30页MDSMDS治疗标准治疗标准治疗方案设计要求个体化、分层治疗方案设计要求个体化、分层personalization stratification;支持、对症治疗仍是主要办法（支持、对症治疗仍是主要办法（Best supportive care)：红细胞、血小板输注，红细胞、血小板输注，CSFs,EPO 抗感染抗感染 去铁治疗去铁治疗FDA同意药品（同意药品（3个）：个）：去甲基化药品去甲基化药品:-阿扎胞苷（阿扎胞苷（5-azacytidine）-地西他滨（地西他滨（decitabine,;中国中国）来那度胺（来那度胺（lenalidomide，）：）：del(5q)首选首选造血干细胞移植造血干细胞移植31骨髓增生异常综合征第31页Hypomethylating Cytosine Analogues地西他地西他宾宾FDA阿扎阿扎胞苷胞苷FDA32骨髓增生异常综合征第32页地西他滨地西他滨（Decitabine，Dacogen)15-30 mg/m2(10-50mg)intravenously daily3-5 days/cycle.33骨髓增生异常综合征第33页Decitabine Pharmacology Mechanism of ActionDecitabine is an S-phase specific agent Antineoplastic activity attributed toInhibition of cell proliferation at higher dosesincorporation into DNA blocking of DNA synthesis cytotoxicitynonreversible covalent linking with DNA methyltransferaseInduction of hypomethylation at lower doses promoting cell differentiationre-expression of tumor suppressor genes stimulation of immune mechanismssuppression of tumor growth 34骨髓增生异常综合征第34页Hypomethylators vs Intensive Chemo Rx in MDS with 10-30%Blasts330 pts:93(28%)Rx with HMA and 237(72%)with chemo Rx MVA:worse survival with chemo RxParameterHMAIntensive Chemo Rxp value%CR+CRp4260.01Median Rem.dur.(mos)14.714.7%8-wk mortality1013median OS(mos)18.814.6.32Nazha.Blood 122:abst 2788:35骨髓增生异常综合征第35页来那度胺来那度胺(Lenalidomide,瑞复美瑞复美)AntiangiogenicImmunomodulatory imide drugs(IMiDs)5q-syndrome10 mg/day orallyMultiple myeloma36骨髓增生异常综合征第36页Thalidomide（沙利度胺（沙利度胺、反应停）、反应停）developed by German pharmaceutical company Grnenthalsold from 1957 to 1961 to pregnant women,as an antiemetic to combat morning sickness and as an aid to help them sleep approximately 10,000 children were born with severe malformities,including phocomelia（Seal Baby)1991 Dr.Gilla Kaplan at Rockefeller University showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha 37骨髓增生异常综合征第37页其它治疗选择其它治疗选择1.免疫抑制剂：免疫抑制剂：ATG,CsA,Dexamethasone2.小剂量化疗：小剂量化疗：Low-dose cytarabine；DA3.亚砷酸亚砷酸4.ATRA5.Amifostine 阿米福汀阿米福汀(氨磷汀氨磷汀)6.Clinical trials38骨髓增生异常综合征第38页预后预后median survival(mo.)RARSRARSRARACMMLCMMLRAEBRAEBRAEB-TRAEB-T0 012122424363648486060Median survival in MDSMedian survival in MDS39骨髓增生异常综合征第39页40骨髓增生异常综合征第40页Prognostic modelsIPSSIPSS-RWPSSOthers:Global MDACC model;MDACC lower risk model;Impact of comorbidities41骨髓增生异常综合征第41页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骨髓增生异常综合征第42页Nybakken&Bagg.Journal of Molecular Diagnostics,;16:145-158 Cytogenetic findings in MDSCytogenetic findings in MDS43骨髓增生异常综合征第43页44骨髓增生异常综合征第44页Distribution of recurrent mutations andkaryotypic abnormalities in MDS45骨髓增生异常综合征第45页Mutational landscape in MDSHaferlach et al.Leukemia 46Targeted sequencing of a limited number of genes can detectmutations in 80%to 90%of MDS patients;the most commonly mutated genes in MDS are SF3B1,TET2,SRSF2,ASXL1,DNMT3A,RUNX1,U2AF1,TP53,and EZH2骨髓增生异常综合征第46页Mutations of TP53&SF3B1TP53 mutation is associated with aggressive disease in MDS in general and appears to predict poorer response to lenalidomide in patients with del(5q).With regard to MDS with ring sideroblasts(MDS-RS),recurrent mutations in the spliceosome gene SF3B1 are frequent in MDS and are associated with the presence of ring sideroblasts.So,if an SF3B1 mutation is identified,a diagnosis of MDS-RS may bemade if ring sideroblasts comprise as few as 5%ofnucleated erythroid cells47骨髓增生异常综合征第47页Impact of mutation of p53 or DNMT3A on survival of MDS pts w/HSC 48骨髓增生异常综合征第48页表观遗传学调控异常表观遗传学调控异常epigenetics不包括基因一级结构改变表示调控机制，即基因DNA序列不发生改变情况下，基因表示水平与功效发生改变，并产生可遗传表型三大特征：DNA序列本身不变、可遗传、可逆性Regulation of transcriptionnDNA methylation 甲基化nHistone modifications 组蛋白修饰nChromatin remodeling nPseudogenes Regulation of post-transcriptionnNon-coding RNA：microRNA,siRNA,lncRNAnRiboswitch49骨髓增生异常综合征第49页DNA甲基化基本作用：抑制基因表示50骨髓增生异常综合征第50页DNA+histones=Nucleosome（转录单位）（转录单位）nAcetylation/deacetylation乙酰化乙酰化-去乙酰化去乙酰化nMethylation/demethylation甲基化甲基化-去甲基化去甲基化nPhosphorylation/dephosphorylation磷酸化状态磷酸化状态组蛋白修饰Histone modifications “histone code”51骨髓增生异常综合征第51页Epigenetic Alterationsmmm mmethylationacetylationphosphorylationDNA methylationHistone modificationsH3 AC K9 +H4 AC K8 +H3 Ser10P +H3Met K4 +H3 Met K9 Histone residue Effect52骨髓增生异常综合征第52页Examples of DNA methylationuDNA replicationuX chromosome inactivationuGenomic imprinting(基因组印记):亲代基因在子代中表示情况取决于基因来自母本还是父本现象。即来自父方和母方等位基因在传递给子代时发生了修饰，使带有亲代印记等位基因含有不一样表示特征。uCancer骨髓增生异常综合征第53页DNA Methylation vs Cancer54骨髓增生异常综合征第54页55骨髓增生异常综合征第55页Methylation of LINE-1 before and after Decitabine treatment Line-1:long interspersed nucleotide elements 56骨髓增生异常综合征第56页57骨髓增生异常综合征第57页DNMTi58骨髓增生异常综合征第58页SAHA(Zolinza)was the first HDACi approved by the FDA for the treatment of cutaneous T cell lymphoma(CTCL)on October 6,HDACi59骨髓增生异常综合征第59页60骨髓增生异常综合征第60页Clinical trials61Luspatercept对SF3B1突变阳性者有效率60%阴性者11%骨髓增生异常综合征第61页62骨髓增生异常综合征第62页63骨髓增生异常综合征第63页