1] Hematology Department, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France [2] Université Paris Diderot (Paris 7), Paris, France [3] INSERM U944, Paris, France.
1] Hematology Department, Hopital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France [2] Université Paris Diderot (Paris 7), Paris, France [3] INSERM UMR-S-940, Paris, France.
Leukemia. 2014 Mar;28(3):497-506. doi: 10.1038/leu.2013.343. Epub 2013 Nov 19.
Myelodysplastic syndromes (MDS) are clonal diseases of the elderly characterized by chronic cytopenias, dysplasia and a variable risk of progression to acute myeloid leukemia (AML). Aberrant methylation of tumor-suppressor gene promoters has been established for many years and recently tracked to the most immature cells of MDS, suggesting that these alterations are drivers of MDS pathogenesis. In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation and in covalent histone modifications have been reported in myeloid malignancies, including MDS. Whole-genome epigenetic profiles of MDS are also emerging. In parallel with these advances in the molecular pathogenesis of MDS, clinical trials have established hypomethylating agents (HMAs) as the mainstay of therapy in the advanced forms of the disease. In this review, we summarize the current understanding of the molecular machinery involved in epigenetic regulation, discuss how epigenetic alterations arise in MDS and contribute to its pathogenesis and then discuss the mode of action of HMAs in MDS.
骨髓增生异常综合征（MDS）是一种老年克隆性疾病，其特征为慢性血细胞减少、发育异常以及向急性髓系白血病（AML）进展的风险可变。多年来，肿瘤抑制基因启动子的异常甲基化已经得到确立，并且最近追踪到 MDS 最不成熟的细胞，这表明这些改变是 MDS 发病机制的驱动因素。近年来，在包括 MDS 在内的髓系恶性肿瘤中已报道涉及 DNA 甲基化和去甲基化以及共价组蛋白修饰的蛋白质编码基因的反复体细胞突变。MDS 的全基因组表观遗传谱也在不断涌现。随着 MDS 分子发病机制的这些进展，临床试验已将低甲基化剂（HMAs）确立为该疾病晚期形式的主要治疗方法。在这篇综述中，我们总结了参与表观遗传调控的分子机制的最新认识，讨论了表观遗传改变如何在 MDS 中产生以及如何促进其发病机制，然后讨论了 HMAs 在 MDS 中的作用模式。
