Albert Einstein College of Medicine, New York, NY, USA.
Semin Hematol. 2013 Jan;50(1):16-37. doi: 10.1053/j.seminhematol.2013.01.001.
The myelodysplastic syndromes (MDS) are a group of hematologic disorders characterized by ineffective hematopoiesis and increased risk of transformation to acute myeloid leukemia (AML). Even though mutations have been shown to occur in MDS, a notable proportion of these affect genes involved in epigenetic maintenance, suggesting a dominant role of epigenomic dysregulation in the pathogenesis of MDS. Aberrant DNA methylation is the dominant and most well-studied epigenetic alteration in MDS. Various genes, including cell cycle regulators, apoptotic genes, and DNA repair genes, are epigenetically silenced and have roles in pathogenesis and transformation to leukemia. The involvement of these genes in MDS pathophysiology and prognosis is reviewed and reveals distinct methylation patterns between high- and low-risk subsets of this disease. Furthermore, DNA methyltransferase (DNMT) inhibitors azacitdine and decitabine are approved for treatment even though the optimal dosing strategies are still being developed. We have reviewed the mechanisms of action of these agents in MDS and show that demethylation may not correlate well with their efficacy, thus suggesting alternative modes of action. We also show that DNMT inhibitors may have potent anti-leukemic stem cell effects at lower doses and also review the mechanisms of resistance to these agents. Altogether, these studies show that even though DNA methylation has been studied extensively in MDS, its role in prognosis and response to therapy is still unclear. The use of deep sequencing and genome-wide methylome analysis will potentially uncover prognostic signatures and reveal the complexity of epigenetic dysregulation in this disease.
骨髓增生异常综合征（MDS）是一组血液疾病，其特征为无效造血和向急性髓系白血病（AML）转化的风险增加。尽管已经证明 MDS 中存在突变，但相当一部分影响涉及表观遗传维持的基因，这表明表观基因组失调在 MDS 的发病机制中起主要作用。异常的 DNA 甲基化是 MDS 中主要且研究最多的表观遗传改变。包括细胞周期调节剂、凋亡基因和 DNA 修复基因在内的各种基因被表观遗传沉默，在发病机制和向白血病转化中发挥作用。本文综述了这些基因在 MDS 病理生理学和预后中的作用，并揭示了该疾病高危和低危亚组之间存在不同的甲基化模式。此外，DNA 甲基转移酶（DNMT）抑制剂阿扎胞苷和地西他滨已被批准用于治疗，尽管仍在开发最佳的给药策略。我们回顾了这些药物在 MDS 中的作用机制，并表明去甲基化可能与它们的疗效相关性不佳，因此提示存在其他作用机制。我们还表明，DNMT 抑制剂在较低剂量下可能对白血病干细胞具有强大的抗白血病作用，并回顾了这些药物的耐药机制。总之，这些研究表明，尽管 DNA 甲基化在 MDS 中已经得到广泛研究，但它在预后和对治疗的反应中的作用仍不清楚。深度测序和全基因组甲基组分析的使用将有可能揭示预后标志物，并揭示该疾病中表观遗传失调的复杂性。
