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1、骨髓增生异常综合骨髓增生异常综合征征（Myelodysplastic syndromes, MDS）1 2 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,sm
2、oulderingleukemia定义定义3 MDSvsAMLBlood. 2013;121:38114 发病情况发病情况发病年龄：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)5 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- 基因水平的改变；基因水平的改变；AML1
3、-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 分类分类FAB: 1976; 1982 中国1986WHO: 2000; 2008; 20167 FAB 1976Dysmyelopoietic syndromesRARAEBBr J Haematol 1976, 33:4518 MDS(FAB1982)% Ringed SideroblastsPB BlastsBM BlastsPB MonocytesRA 1% 15% 1% 5%RAEB 5%21
4、-30%CMML 1x109 /L9 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/MPD10 WHO 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 Cy
5、topenia ( 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 Minimal Diagnostic Criteria in MDS(A)Prerequisite criteriaConstant cytopenia in one or more of the following cell linea
6、ges: 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 2007:727-73629 Minimal Diagnostic Crit
7、eria in MDS Contd.(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 populatio
8、n 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 2007:727-73630 MDS治治疗原原则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pers
9、onalization stratification; 支持、对症治疗仍是主要措施（支持、对症治疗仍是主要措施（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批准的药物（批准的药物（3个）：个）： 去甲基化药物去甲基化药物: - 阿扎胞苷（阿扎胞苷（5-azacytidine 2004） - 地西他滨（地西他滨（decitabine, 2006; 中国中国2009） 来那度胺（来那度胺（ lenalidomide，2005）：）：del(5q) 首选首选造血干细胞移植造血干细胞移植31 Hypome
10、thylating Cytosine Analogues地西他宾地西他宾FDA2006阿扎胞苷阿扎胞苷FDA200432 地西他滨地西他滨 （Decitabine，Dacogen) 15-30 mg/m2 (10-50mg) intravenously daily3-5 days/cycle. 33 Decitabine Pharmacology Mechanism of ActionDecitabine is an S-phase specific agent Antineoplastic activity attributed toInhibition of cell proliferat
11、ion 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 tu
12、mor growth 34 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)18.814.6.32Na
13、zha. Blood 122: abst 2788: 201335 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 Thalidomide（沙利度胺（沙利度胺、反应停）、反应停）developedbyGermanpharmaceuticalcompanyGrnenthalsoldfrom1957to1961topregnantwomen,asanantiemetictocombatmornin
14、gsicknessandasanaidtohelpthemsleepapproximately10,000childrenwerebornwithseveremalformities,includingphocomelia（SealBaby)1991Dr.GillaKaplanatRockefellerUniversityshowedthatthalidomideworkedinleprosybyinhibitingtumornecrosisfactoralpha37 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：
15、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 预后预后39 40 Prognostic modelsIPSSIPSS-RWPSSOthers:GlobalMDACCmodel;MDACClowerriskmodel;Impactofcomorbidities41 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42 Nybakken & Bagg. Journal of Molecular Diagnostics, 2014; 16:145-1
16、58 CytogeneticfindingsinMDS43 44 DistributionofrecurrentmutationsandkaryotypicabnormalitiesinMDS45 MutationallandscapeinMDSHaferlach et al. Leukemia 201346Targeted sequencing of a limited number of genes can detectmutations in 80% to 90% of MDS patients; the most commonly mutated genes in MDS are SF
17、3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2 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 m
18、utations 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 Impactofmutationofp53orDNMT3Aonsurvi
19、valofMDSptsw/HSC48 表观遗传学调控异常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RegulationoftranscriptionnDNAmethylation甲基化nHistonemodifications组蛋白修饰nChromatinremodelingnPseudogenesRegulationofpost-transcriptionnNon-codingRNA：microRNA,siRNA,lncRNAnR
20、iboswitch49 DNA甲基化的基本作用：抑制基因表达50 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Histonemodifications“histonecode”51 EpigeneticAlterationsmmm mmethylationacetylationphosphorylatio
21、nDNA methylationHistone modificationsH3 AC K9 +H4 AC K8 +H3 Ser10P +H3Met K4 +H3 Met K9 Histone residue Effect52 Examples 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。uCancer53 DNA
22、 Methylation vs Cancer54 55 Methylation of LINE-1 before and after Decitabine treatment Line-1: long interspersed nucleotide elements 56 57 DNMTi58 SAHA(Zolinza) was the first HDACi approved by the FDA for the treatment of cutaneous T cell lymphoma (CTCL) on October 6, 2006HDACi59 60 Clinicaltrials61Luspatercept对SF3B1突变阳性者有效率60%阴性者11% 62 63
