Jhanwar Suresh C
Departments of Pathology and Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
Adv Biol Regul. 2015 May;58:28-37. doi: 10.1016/j.jbior.2014.11.002. Epub 2014 Nov 20.
Myelodysplastic syndromes (MDS) are a highly heterogenous group of hematopoietic tumors, mainly due to variable clinical features and diverse set of cytogenetic, molecular genetic and epigenetic lesions. The major clinical features of MDS are ineffective hematopoiesis, peripheral cytopenias, and an increased risk of transformation to acute myeloid leukemias, which in turn is most likely determined by specific genetic abnormalities and other presenting hematologic features. The risk of developing MDS is relatively higher in some genetic syndromes such as Fanconi anemia and receipt of chemotherapy and radiation treatment. In recent years a significant progress has occurred and a vast literatures has become available including the spectrum of cytogenetic abnormalities, gene mutations relating to RNA splicing machinery, epigenetic regulation of gene expression and signaling pathways associated with MDS pathogenesis, which have provided opportunities to understand the molecular mechanisms as well as employ targeted therapeutic approaches to treat MDS. The cytogenetic abnormalities detected in MDS varies from a single abnormality to complex karyotype not easily amenable to conventional cytogenetic analysis. In such cases, array based high resolution genomic analysis detected abnormalities, which are diagnostic as well as prognostic. The most common driver gene mutations detected in patients with MDS include RNA splicing (SF3B1,SRSF2,U2F1,ZRSR2), DNA methylation (TET2,DNMT3A,IDH1/IDH2), chromatin modification (ASXL1,EZH2), transcription regulation (RUNX1,BCOR) and DNA repair control p53. A small subset of MDS arise due to deregulation of RAS pathway, mainly due to NRAS/KRAS/NF1 mutations. Identification of these mutations and pathways have provided opportunities for oncologists to target these patients with specific therapies. Several drugs which either target the spliceosome, oncogenic RAS signaling, or hypomethylating agents have been employed to successfully treat MDS patients.
骨髓增生异常综合征（MDS）是一组高度异质性的造血肿瘤，主要归因于临床特征不一以及细胞遗传学、分子遗传学和表观遗传学病变的多样性。MDS的主要临床特征为造血无效、外周血细胞减少以及转化为急性髓系白血病的风险增加，而这反过来很可能由特定的基因异常和其他血液学表现特征所决定。在某些遗传综合征（如范可尼贫血）以及接受化疗和放疗的情况下，发生MDS的风险相对较高。近年来已取得显著进展，有大量文献可供参考，内容涵盖细胞遗传学异常谱、与RNA剪接机制相关的基因突变、基因表达的表观遗传调控以及与MDS发病机制相关的信号通路，这些都为了解分子机制以及采用靶向治疗方法治疗MDS提供了机会。在MDS中检测到的细胞遗传学异常从单一异常到复杂核型不等，传统细胞遗传学分析难以对其进行分析。在这种情况下，基于阵列的高分辨率基因组分析可检测到具有诊断和预后价值的异常。在MDS患者中检测到的最常见驱动基因突变包括RNA剪接（SF3B1、SRSF2、U2F1、ZRSR2）、DNA甲基化（TET2、DNMT3A、IDH1/IDH2）、染色质修饰（ASXL1、EZH2）、转录调控（RUNX1、BCOR）以及DNA修复控制p53。一小部分MDS是由于RAS通路失调引起的，主要是由于NRAS/KRAS/NF1突变。这些突变和通路的鉴定为肿瘤学家针对这些患者采用特定疗法提供了机会。几种靶向剪接体、致癌RAS信号或去甲基化药物已被用于成功治疗MDS患者。
