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1、骨髓增生异常骨髓增生异常综合合征征（Myelodysplastic syndromes, MDS）a2a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,smou
2、lderingleukemia定定义3aMDSvsAMLBlood. 2013;121:3811a发病情况病情况发病年龄：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)5a高高龄，外因；，外因；原原发性、性、继发性性MDS：tMDS（烷化化剂、表鬼臼毒素、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、增生失控、分化受阻、细胞凋亡增加胞凋亡增加细胞胞遗传学异常：学异常：-5/5q-，-7/7q- 基因水平的改基因水平的改变；AML1-MDS1-EVI1融合基因融合基因表表
3、观遗传学学调控异常控异常病因、病因、发病机理病机理MDSMPNLeukemiaProliferationDifferentiation Apoptosis6a分分类FAB: 1976; 1982 中国1986WHO: 2000; 2008; 20167aFAB 1976Dysmyelopoietic syndromesRARAEBBr J Haematol 1976, 33:4518aMDS(FAB1982)% Ringed SideroblastsPB BlastsBM BlastsPB MonocytesRA 1% 15% 1% 5%RAEB 5%21-30%CMML 1x109 /L9a
4、FABWHO 2000 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%也应诊断为白血病lCMML: MDS/MPD10aWHO 2000 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),
5、 Transfusion-dependent, macrocytic anemia Hgb 10g/dL ANC 1.5 x 109/L PLT 50%MDS with hypocellular marrow MDS with fibrosisMDS with thrombocytosisPNHMPNAAMDSAML28aMinimal Diagnostic Criteria in MDS(A)Prerequisite criteriaConstant cytopenia in one or more of the following cell lineages: erythroid (hem
6、oglobulin 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 2007:727-73629aMinimal Diagnostic Criteria in MDS Contd.(
7、C) Co-criteria (for patients fulfilling A but not B”): Typical clinical features, macrocytic transfusion-dependent anemia. 典型临床特征，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,
8、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 2007:727-73630aMDS治治疗原原则治治疗方案方案设计要求个体化、分要求个体化、分层personalization stratificat
9、ion; 支持、支持、对症治症治疗仍是主要措施（仍是主要措施（Best supportive care)： 红细胞、血小板胞、血小板输注，注，CSFs, EPO 抗感染抗感染 去去铁治治疗FDA批准的批准的药物（物（3个）：个）： 去甲基化去甲基化药物物: - 阿扎胞苷（阿扎胞苷（5-azacytidine 2004） - 地西他地西他滨（decitabine, 2006; 中国中国2009） 来那度胺（来那度胺（ lenalidomide，2005）：）：del(5q) 首首选造血干造血干细胞移植胞移植31aHypomethylating Cytosine Analogues地西他地西他宾F
10、DA2006阿扎胞苷阿扎胞苷FDA200432a地西他地西他滨 （Decitabine，Dacogen) 15-30 mg/m2 (10-50mg) intravenously daily3-5 days/cycle. 33aDecitabine Pharmacology Mechanism of ActionDecitabine is an S-phase specific agent Antineoplastic activity attributed toInhibition of cell proliferation at higher dosesincorporation into
11、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 34aHypomethylators vs Inten
12、sive 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: 201335a来那度胺
13、来那度胺(Lenalidomide,瑞复美瑞复美)AntiangiogenicImmunomodulatory imide drugs (IMiDs)5q- syndrome10 mg/day orallyMultiple myeloma36aThalidomide（沙利度胺（沙利度胺、反、反应停）停）developedbyGermanpharmaceuticalcompanyGrnenthalsoldfrom1957to1961topregnantwomen,asanantiemetictocombatmorningsicknessandasanaidtohelpthemsleepappro
14、ximately10,000childrenwerebornwithseveremalformities,includingphocomelia（SealBaby)1991Dr.GillaKaplanatRockefellerUniversityshowedthatthalidomideworkedinleprosybyinhibitingtumornecrosisfactoralpha37a其它治其它治疗选择1.免疫抑制免疫抑制剂：ATG, CsA, Dexamethasone2.小小剂量化量化疗：Low-dose cytarabine；DA3.亚砷酸砷酸4.ATRA5.Amifostine
15、 阿米福汀阿米福汀(氨磷汀氨磷汀)6.Clinical trials38a预后后39a40aPrognostic modelsIPSSIPSS-RWPSSOthers:GlobalMDACCmodel;MDACClowerriskmodel;Impactofcomorbidities41a发病机制及分子治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aNybakken & Bagg. Journal of Molecular Diagnostics, 2014; 16:145-158 CytogeneticfindingsinMDS43a44aDistributio
16、nofrecurrentmutationsandkaryotypicabnormalitiesinMDS45aMutationallandscapeinMDSHaferlach et al. Leukemia 2013Targeted 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,
17、 TP53, and EZH246aMutations 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 f
18、requent 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 cells47aImpactofmutationofp53orDNMT3AonsurvivalofMDSptsw/HSC48a表表观遗传学学调控异常控异常epigenetics
19、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RegulationoftranscriptionnDNAmethylation甲基化nHistonemodifications组蛋白修饰nChromatinremodelingnPseudogenesRegulationofpost-transcriptionnNon-codingRNA：microRNA,siRNA,lncRNAnRiboswitch49aDNA甲基化的基本作用：抑制基因表达50aDNA+histones =
20、Nucleosome （转录单位）位）nAcetylation/deacetylation乙乙酰化化-去乙去乙酰化化nMethylation/demethylation甲基化甲基化-去甲基化去甲基化nPhosphorylation/dephosphorylation磷酸化状磷酸化状态组蛋白修饰Histonemodifications“histonecode”51aEpigeneticAlterationsmmm mmethylationacetylationphosphorylationDNA methylationHistone modificationsH3 AC K9 +H4 AC K8
21、 +H3 Ser10P +H3Met K4 +H3 Met K9 Histone residue Effect52aExamples of DNA methylationuDNA replicationuX chromosome inactivationuGenomic imprinting(基因组印记): 亲代基因在子代中表达状况取决于基因来自母本还是父本的现象。即来自父方和母方的等位基因在传递给子代时发生了修饰，使带有亲代印记的等位基因具有不同的表达特性。uCanceraDNA Methylation vs Cancer54a55aMethylation of LINE-1 before and after Decitabine treatment Line-1: long interspersed nucleotide elements 56a57aDNMTi58aSAHA(Zolinza) was the first HDACi approved by the FDA for the treatment of cutaneous T cell lymphoma (CTCL) on October 6, 2006HDACi59a60aClinicaltrialsLuspatercept对SF3B1突变阳性者有效率60%阴性者11%61a62a63a
