骨髓增生异常综合征PPT课件

1、骨髓增生异常综合征（Myelodysplastic syndromes, MDS）,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。 A group of clonal neoplasms; heterogeneous; Hematopoietic stem cells (HSC) or progenitors; Cytopenia Myelodysplasia; ineffective hematopoiesis Increased risk of blastic transformation: -

2、preleukemia, smouldering leukemia,定义,3,MDS vs AML,Blood. 2013;121:3811,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),5,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MDS HSC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,6,分类

3、,FAB: 1976; 1982 中国1986 WHO: 2000; 2008; 2016,7,FAB 1976,Dysmyelopoietic syndromes RA RAEB,Br J Haematol 1976, 33:451,8,MDS (FAB 1982),9,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,10,WHO 2000,WHO 20002008,增加RN、RT，与RA一起组成RCUD; 重新定

4、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）,12,WHO 2008,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 multilineage

5、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),14,15,CHIP Dyserythropoiesis; Dysgranulopoiesis; Dysmegakaryopoiesis Trephine biopsy: Cellularity; Myelofib

6、rosis (reticulin, MDS with fibrosis); Report estimated % of CD34+ blasts; Dysmegakaryopoiesis (CD61); ALIP(abnormal localized immature precursors),23,红系病态造血,Normal,Ringed sideroblasts,24,粒系病态造血,25,巨核系病态造血,26,诊断、鉴别诊断,PB：cytopenia(s) BM smear：dysplasia BM biopsy：ALIP Flow cytometry Cytogenetic：5q-/-5,

7、 -7 Molecular：NGS MA, AA, PNH, MPN, AML,27,28,Minimal Diagnostic Criteria in MDS,Prerequisite criteria Constant cytopenia in one or more of the following cell lineages: erythroid (hemoglobulin 15% ringed sideroblasts 5-19% Blast cells in bone marrow smears Typical chromosomal abnormality: convention

8、al karyotyping or FISH,Valent P, et al. Leukemia Research 2007:727-736,29,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 o

9、f 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-assa

10、y)骨髓集落培养减低,Valent P, et al. Leukemia Research 2007:727-736,30,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

11、造血干细胞移植,31,Hypomethylating Cytosine Analogues,地西他宾 FDA2006,阿扎胞苷 FDA2004,32,2020/7/7,33,.,地西他滨 （Decitabine，Dacogen),15-30 mg/m2 (10-50mg) intravenously daily 3-5 days/cycle.,34,Decitabine Pharmacology Mechanism of Action,Decitabine is an S-phase specific agent Antineoplastic activity attributed to In

12、hibition 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 suppressor genes stimulation of imm

13、une mechanisms suppression of tumor growth,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: 2013,36,来那度胺(Lenalidomide,瑞复美),Antiangiogenic Immunomodulatory imide

14、drugs (IMiDs) 5q- syndrome 10 mg/day orally Multiple myeloma,37,Thalidomide（沙利度胺、反应停）,developed by German pharmaceutical company 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 wi

15、th 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,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 ATRA Amifostine 阿米福汀(氨磷汀) Clinical tr

16、ials,39,预后,40,41,Prognostic models,IPSS IPSS-R WPSS Others: Global MDACC model; MDACC lower risk model; Impact of comorbidities,42,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,Nybakken 16:145-158,Cytogenetic findings in MDS,44,45,Distribution of recurrent mutations andkaryotypic abnormalities in MDS,46

17、,Mutational landscape in MDS,Haferlach et al. Leukemia 2013,47,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,Mutations of TP53 & SF3B1,TP53

18、 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 pre

19、sence 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% of nucleated erythroid cells,48,Impact of mutation of p53 or DNMT3A on survival of MDS pts w/ HSC,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

20、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 Regulation of transcription DNA methylation 甲基化 Histone modifications 组蛋白修饰 Chromatin remodeling Pseudogenes Regulation of post-transcription Non-coding RNA：microRNA, siRNA, lncRNA Riboswitch,50,DNA甲基化的基本作用：抑制基因表达,51,DNA+histones = Nucleosome （转录单位） Acetylation/deacetylation乙酰化-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”,52,Epigenetic Alterations,m,m,m,m,methylation,acetylation,phosph