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1、a,骨髓增生异常综合征（Myelodysplastic syndromes, MDS）,a,2,a,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。A group of clonal neoplasms; heterogeneous;Hematopoietic stem cells (HSC) or progenitors; CytopeniaMyelodysplasia; ineffective hematopoiesisIncreased risk of blastic transformation
2、: - preleukemia, smouldering leukemia,定义,a,MDS vs AML,Blood. 2013;121:3811,a,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 (Int J Hematol 2001,73:405),a,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,
3、a,7,分类,FAB: 1976; 1982 中国1986WHO: 2000; 2008; 2016,a,8,FAB 1976,Dysmyelopoietic syndromesRARAEB,Br J Haematol 1976, 33:451,a,9,MDS (FAB 1982),a,10,FABWHO 2000,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,a,WHO 2000,a,12,WHO 20002008,增加RN、RT，与RA
4、一起组成RCUD; 重新定义MDS-U（不再包括RN和RT）增加Childhood MDS （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）,a,WHO 2008,a,14,WHO 2016,MDS with single lineage dysplasia (MDS-SLD)MDS with multilineage dysplasia (MDS-MLD)MDS with ring sideroblasts (MDS-RS)MDS-RS and single lineage dysplasia (MDS-RSSLD)MDS-RS and mul
5、tilineage dysplasia (MDS-RSMLD)MDS with excess blasts (MDS-EB1, MDS-EB2)MDS with isolated del(5q) (5q- syndrome)MDS, unclassifiable (MDS-U)Provisional entity: Refractory cytopenia of childhood (RCC),a,15,a,16,CHIP & ICUS,Clonal hematopoiesis of indeterminate potential (CHIP): acquired clonal mutatio
6、ns identical to those seen in MDS can occur in the hematopoietic cells of apparently healthy older individuals without MDS. Provisional category：idiopathic cytopenia of undetermined significance (ICUS),a,17,a,18,Myeloproliferative neoplasms (MPN)MastocytosisMyeloid/lymphoid neoplasms with eosinophil
7、ia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)Myelodysplastic syndromes (MDS)Myeloid neoplasms with germ line predispositionAcute myeloid leukemia (AML) and related neoplasmsAML with recurrent genetic abnormalitiesAML with my
8、elodysplasia-related changesTherapy-related myeloid neoplasmsAML, NOSMyeloid sarcomaMyeloid proliferations related to Down syndromeTransient abnormal myelopoiesis (TAM)Myeloid leukemia associated with Down syndromeAcute leukemias of ambiguous lineageB-lymphoblastic leukemia/lymphomaT-lymphoblastic l
9、eukemia/lymphomaProvisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymphoma,WHO myeloid neoplasm and acute leukemia classification,a,19,Myeloproliferative neoplasms (MPN)(JAK2, MPL, CALR mutations),Chronic myeloid leukemia (CML), BCR-ABL11Chronic neutrophilic leukemia (CNL) (CSF3R m
10、utation)Polycythemia vera (PV)Primary myelofibrosis (PMF)PMF, prefibrotic/early stagePMF, overt fibrotic stageEssential thrombocythemia (ET) Chronic eosinophilic leukemia, not otherwise specified (NOS)MPN, unclassifiable,a,20,Myelodysplastic/myeloproliferative neoplasms (MDS/MPN),Chronic myelomonocy
11、tic leukemia (CMML)Atypical chronic myeloid leukemia (aCML), BCR-ABL1(-)Juvenile myelomonocytic leukemia (JMML)MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)MDS/MPN, unclassifiable,a,临床表现,差异大、早期低危患者无症状贫血发热、感染出血一般无肝脾淋巴结肿大转化为急性白血病老年患者多有合并症,a,22,Recommendations and Definitions in MDS,
12、Recommendations Differential: 500 in BM, 200 cells in PB Number: 200 for G and E, 30 cells for meg. Ring sideroblasts: 5 iron granules encircling 1/3 of the nucleus Minimal dysplastic changes (good quality of smear) 10% in one single cell line* or 10% with recurrent abnormal cytogenetics Cytopenia (
13、 6 month), Transfusion-dependent, macrocytic anemia Hgb 10g/dL ANC 1.5 x 109/L PLT 100 x 109/L Constant blast count 5-19%,a,23,Morphologic Features,Blasts：MyeloblastsDysmyelopoiesis; Dyserythropoiesis; Dysgranulopoiesis; DysmegakaryopoiesisTrephine biopsy: Cellularity; Myelofibrosis (reticulin, MDS
14、with fibrosis); Report estimated % of CD34+ blasts; Dysmegakaryopoiesis (CD61); ALIP(abnormal localized immature precursors),a,24,红系病态造血,Normal,Ringed sideroblasts,a,25,粒系病态造血,a,26,巨核系病态造血,a,27,诊断、鉴别诊断,PB：cytopenia(s)BM smear：dysplasiaBM biopsy：ALIPFlow cytometryCytogenetic：5q-/-5, -7Molecular：NGSMA
15、, AA, PNH, MPN, AML,a,28,a,29,Minimal Diagnostic Criteria in MDS,Prerequisite criteriaConstant cytopenia in one or more of the following cell lineages: erythroid (hemoglobulin 15% ringed sideroblasts5-19% Blast cells in bone marrow smearsTypical chromosomal abnormality: conventional karyotyping or F
16、ISH,Valent P, et al. Leukemia Research 2007:727-736,a,30,Minimal 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 pop
17、ulation 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,
18、 et al. Leukemia Research 2007:727-736,a,31,MDS治疗原则,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（Best supportive care)： 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-azacytidine 2004） - 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,a,32,Hypomet
19、hylating Cytosine Analogues,地西他宾FDA2006,阿扎胞苷FDA2004,a,33,地西他滨 （Decitabine，Dacogen),15-30 mg/m2 (10-50mg) intravenously daily3-5 days/cycle.,a,34,Decitabine Pharmacology Mechanism of Action,Decitabine is an S-phase specific agent Antineoplastic activity attributed toInhibition of cell proliferation a
20、t 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 g
21、rowth,a,35,Hypomethylators vs Intensive Chemo Rx in MDS with 10-30% Blasts,330 pts: 93 (28%) Rx with HMA and 237 (72%) with chemo Rx MVA: worse survival with chemo Rx,Nazha. Blood 122: abst 2788: 2013,a,36,来那度胺(Lenalidomide,瑞复美),AntiangiogenicImmunomodulatory imide drugs (IMiDs)5q- syndrome10 mg/day
22、 orallyMultiple myeloma,a,37,Thalidomide（沙利度胺、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 ph
23、ocomelia（ Seal Baby ) 1991 Dr. Gilla Kaplan at Rockefeller University showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha,a,38,其它治疗选择,免疫抑制剂：ATG, CsA, Dexamethasone小剂量化疗：Low-dose cytarabine；DA亚砷酸ATRAAmifostine 阿米福汀(氨磷汀)Clinical trials,a,39,预后,a,40,a,41,Prognostic model
24、s,IPSSIPSS-RWPSSOthers: Global MDACC model; MDACC lower risk model; Impact of comorbidities,a,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,a,43,Nybakken 16:145-158,Cytogenetic findings in MDS,a,44,a,45,Distribution of recurrent mutations andkaryotypic abnormalities in MDS,a,46,Mutational landscape in MDS
25、,Haferlach et al. Leukemia 2013,Targeted 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,a,47,Mutations of TP53 & SF3B1,TP53 mutation is associated wi
26、th 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.
27、 So, if an SF3B1 mutation is identified, a diagnosis of MDS-RS may bemade if ring sideroblasts comprise as few as 5% ofnucleated erythroid cells,a,48,Impact of mutation of p53 or DNMT3A on survival of MDS pts w/ HSC,a,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
28、的表型三大特征： DNA序列本身不变、可遗传、可逆性Regulation of transcriptionDNA methylation 甲基化Histone modifications 组蛋白修饰Chromatin remodeling Pseudogenes Regulation of post-transcriptionNon-coding RNA：microRNA, siRNA, lncRNARiboswitch,a,50,DNA甲基化的基本作用：抑制基因表达,a,51,DNA+histones = Nucleosome （转录单位）Acetylation/deacetylation乙
29、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Histone modifications “histone code”,a,52,Epigenetic Alterations,m,m,m,m,methylation,acetylation,phosphorylation,DNA methylation,Histone modifications,H3 AC K9 +H4 AC K8 +H3 Ser10P +H3Met K4 +H3 Met K9 ,Histone resid
30、ue Effect,a,Examples of DNA methylation,DNA replicationX chromosome inactivationGenomic 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。Cancer,a,54,DNA Methylation vs Cancer,a,55,a,56,Methylation of LINE-1 before and after Decitabine treatment,Line-1: long interspersed nucleotide elements,a,57,a,58,DNMTi,a,59,SAHA(Zolinza) was the first HDACi approved by the FDA for the treatment of cutaneous T cell lymphoma (CTCL) on October 6, 2006,HDACi,a,60,a,61,Clinical trials,Luspatercept对SF3B1突变阳性者有效率60%阴性者11%,a,62,a,63,Thank you!,
