1、a骨髓增生异常综合骨髓增生异常综合征征（Myelodysplastic syndromes, MDS）a2a3一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。 A group of clonal neoplasms; heterogeneous; Hematopoietic stem cells (HSC) or progenitors; Cytopenia Myelodysplasia; ineffective hematopoiesis Increased risk of blastic transfo
2、rmation: - preleukemia, smouldering leukemia定义定义aMDS vs AMLBlood. 2013;121:3811a5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 (Int J Hematol 2001,73:405)a6 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MDS HSC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
3、传学异常：-5/5q-，-7/7q- 基因水平的改变；基因水平的改变；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MDSMPNLeukemiaProliferationDifferentiation Apoptosisa7分类分类 FAB: 1976; 1982 中国1986 WHO: 2000; 2008; 2016a8FAB 1976Dysmyelopoietic syndromes RA RAEBBr J Haematol 1976, 33:451a9MDS (FAB 1982)MDS (FAB 1982)% Ringed SideroblastsP
4、B BlastsBM BlastsPB MonocytesRA 1% 15% 1% 5%RAEB 5%21-30%CMML 1x109 /La10FABWHO 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/MPDaWHO 2000 PB blastsBM blasts 1RA5%5% low risk2RARSRS15% 3RCMD4RCMD-RSRS15%5Del(5q)6RAEB-1 10% in one single cell
5、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 thrombocytosisPNHMPNAAMDSAMLa29Minimal Diagnostic Criteria in MDSPrerequisite criteriaConstant cyt
6、openia 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. Leukemi
7、a Research 2007:727-736a30Minimal Diagnostic Criteria 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 cytom
8、etry 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 2007:72
9、7-736a31MDSMDS治疗原则治疗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personalization 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（ le
10、nalidomide，2005）：）：del(5q) 首选首选造血干细胞移植造血干细胞移植a32Hypomethylating Cytosine Analogues地西他宾地西他宾FDA2006阿扎胞苷阿扎胞苷FDA2004a33地西他滨地西他滨 （Decitabine，Dacogen) 15-30 mg/m2 (10-50mg) intravenously daily 3-5 days/cycle. a34Decitabine Pharmacology Mechanism of ActionDecitabine is an S-phase specific agent Antineoplas
11、tic activity attributed to Inhibition of cell proliferation at higher doses incorporation into DNA blocking of DNA synthesis cytotoxicity nonreversible covalent linking with DNA methyltransferase Induction of hypomethylation at lower doses promoting cell differentiation re-expression of tumor suppre
12、ssor genes stimulation of immune mechanisms suppression of tumor growth a35Hypomethylators 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.
13、(mos)14.714.7% 8-wk mortality1013median OS (mos)18.814.6.32Nazha. Blood 122: abst 2788: 2013a36来那度胺来那度胺(Lenalidomide,瑞复美瑞复美) Antiangiogenic Immunomodulatory imide drugs (IMiDs) 5q- syndrome 10 mg/day orally Multiple myelomaa37Thalidomide（沙利度胺（沙利度胺、反应停）、反应停） developed by German pharmaceutical company
14、 Grnenthal sold 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 thalidomid
15、e worked in leprosy by inhibiting tumor necrosis factor alpha a38其它治疗选择其它治疗选择免疫抑制剂：免疫抑制剂：ATG, CsA, Dexamethasone小剂量化疗：小剂量化疗：Low-dose cytarabine；DA亚砷酸亚砷酸ATRAAmifostine 阿米福汀阿米福汀(氨磷汀氨磷汀)Clinical trialsa39预后预后a40a41Prognostic models IPSS IPSS-R WPSS Others: Global MDACC model; MDACC lower risk model; Im
16、pact of comorbiditiesa发病机制及分子治疗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a43Nybakken & Bagg. Journal of Molecular Diagnostics, 2014; 16:145-158 Cytogenetic findings in MDSCytogenetic findings in MDSa44a45Distribution of recurrent mutations andkaryotypic abnormalities in MDSa46Mutational landscape in MDS
17、Haferlach 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, TP53, and EZH2a47Mutations of TP53 & SF3B1 TP53 mutation is associated with ag
18、gressive 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,
19、 if an SF3B1 mutation is identified, a diagnosis of MDS-RS may bemade if ring sideroblasts comprise as few as 5% of nucleated erythroid cellsa48Impact of mutation of p53 or DNMT3A on survival of MDS pts w/ HSC a49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
20、的表型三大特征： 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, lncRNAnRiboswitcha50DNA甲基化的基本作用：抑制基因表达a51DNA+histones = Nucleosome （转录单位）（转录单位）n Acetylation/deacet
21、ylation乙酰化乙酰化-去乙酰化去乙酰化n Methylation/demethylation甲基化甲基化-去甲基化去甲基化n Phosphorylation/dephosphorylation磷酸化状态磷酸化状态组蛋白修饰Histone modifications “histone code”a52Epigenetic Alterationsmmm mmethylationacetylationphosphorylationDNA methylationHistone modificationsH3 AC K9 +H4 AC K8 +H3 Ser10P +H3Met K4 +H3 Met
22、 K9 Histone residue EffectaExamples of DNA methylationu DNA replicationu X chromosome inactivationu Genomic 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。u Cancera54DNA Methylation vs Cancera55a56Methylation of LINE-1 before and after Decitabine trea
23、tment Line-1: long interspersed nucleotide elements a57Fold changes of gene expression after DAC treatment (D8/D0)0.000.010.101.0010.00100.001000.0010000.00#5#6#7#8#9#10#11#12#13#14#15#18#19#20#21#24#26#27#28#29#30#31#32#33#34#36#37#38#39#40#42#43#44#45#47#48#50#51#53#55#56#59#60#61#63#64#65CalcitoninIRF-12,5-OASp15p16p21RARbetaa58DNMTia59SAHA(Zolinza) was the first HDACi approved by the FDA for the treatment of cutaneous T cell lymphoma (CTCL) on October 6, 2006HDACia60a61Clinical trialsLuspatercept对SF3B1突变阳性者有效率60%阴性者11%a62a63Thank you!
