The plethora of knowledge gained on myelodysplastic syndromes (MDS), a heterogeneous pre-malignant disorder of hematopoietic stem cells, through sequencing of several pathway genes has unveiled molecular pathogenesis and its progression to AML. Evolution of phenotypic classification and risk-stratification based on peripheral cytopenias and blast count has moved to five-tier risk-groups solely concerning chromosomal aberrations. Increased frequency of complex abnormalities, which is associated with genetic instability, defines the subgroup of worst prognosis in MDS. However, the independent effect of monosomal karyotype remains controversial. Recent discoveries on mutations in RNA-splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1, U2AF2); DNA methylation (TET2, DNMT3A, IDH1/2); chromatin modification (ASXL1, EZH2); transcription factor (TP53, RUNX1); signal transduction/kinases (FLT3, JAK2); RAS pathway (KRAS, NRAS, CBL, NF1, PTPN11); cohesin complex (STAG2, CTCF, SMC1A, RAD21); DNA repair (ATM, BRCC3, DLRE1C, FANCL); and other pathway genes have given insights into the independent effects and interaction of co-occurrence of mutations on disease-phenotype. RNA-splicing and DNA methylation mutations appeared to occur early and are reported as 'founder' mutations in over 50% MDS patients. TET2 mutation, through altered DNA methylation, has been found to have independent prognostic response to hypomethylating agents. Moreover, presence of DNMT3A, TET2 and ASXL1 mutations in normal elderly individuals forms the basis of understanding that accumulation of somatic mutations may not cause direct disease-development; however, cooperation with other mutations in the genes that are frequently mutated in myeloid and other hematopoietic cancers might result in clonal expansion through self-renewal and/or proliferation of hematopoietic stem cells. Identification of small molecules as inhibitors of epigenetic mutations has opened avenues for tailoring targeted drug development. The recommendations of a Clinical Advisory Committee is being considered by WHO for a revised classification of risk-groups of MDS, which is likely to be published in mid 2016, based on the new developments and discoveries of gene mutations.

中文翻译：

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骨髓增生异常综合症（MDS）突变：更新。

通过对几种途径基因的测序，获得了关于骨髓增生异常综合症（MDS）（一种造血干细胞异质性恶性疾病）的丰富知识，揭示了分子发病机制及其向AML的发展。基于外周血细胞减少和原始细胞计数的表型分类和风险分层的演变已转移到仅涉及染色体畸变的五级风险组。复杂异常的发生频率增加，这与遗传不稳定有关，定义了MDS预后最差的亚组。但是，单体核型的独立作用仍存在争议。RNA剪接机制突变的最新发现（SF3B1，SRSF2，ZRSR2，U2AF1，U2AF2）；DNA甲基化（TET2，DNMT3A，IDH1 / 2）；染色质修饰（ASXL1，EZH2）; 转录因子（TP53，RUNX1）; 信号转导/激酶（FLT3，JAK2）；RAS途径（KRAS，NRAS，CBL，NF1，PTPN11）；粘着蛋白复合物（STAG2，CTCF，SMC1A，RAD21）; DNA修复（ATM，BRCC3，DLRE1C，FANCL）; 以及其他途径的基因已经深入了解了突变对疾病表型的独立影响和共存相互作用。RNA剪接和DNA甲基化突变似乎较早发生，据报道在50％以上的MDS患者中是“奠基者”突变。已经发现，通过改变DNA甲基化，TET2突变对低甲基化药物具有独立的预后反应。此外，正常老年人中DNMT3A，TET2和ASXL1突变的存在构成了认识，即体细胞突变的积累可能不会导致直接的疾病发展，这是基础。然而，与其他在髓样和其他造血癌症中经常突变的基因中的其他突变的合作可能通过造血干细胞的自我更新和/或增殖而导致克隆扩增。小分子作为表观遗传突变的抑制剂的鉴定为定制靶向药物开发开辟了途径。世卫组织正在考虑临床咨询委员会的建议，以对MDS危险人群进行修订，并根据基因突变的新发展和发现，该分类可能于2016年中期发布。小分子作为表观遗传突变的抑制剂的鉴定为定制靶向药物开发开辟了途径。世卫组织正在考虑临床咨询委员会的建议，以对MDS危险人群进行修订，并根据基因突变的新发展和发现，该分类可能于2016年中期发布。小分子作为表观遗传突变的抑制剂的鉴定为定制靶向药物开发开辟了道路。世卫组织正在考虑临床咨询委员会的建议，以对MDS危险人群进行修订，并根据基因突变的新发展和发现，该分类可能于2016年中期发布。