Human Oncology and Pathogenesis Program, and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Blood. 2013 May 2;121(18):3563-72. doi: 10.1182/blood-2013-01-451781.
Recent studies of the spectrum of somatic genetic alterations in acute myeloid leukemia (AML) have identified frequent somatic mutations in genes that encode proteins important in the epigenetic regulation of gene transcription. This includes proteins involved in the modification of DNA cytosine residues and enzymes which catalyze posttranslational modifications of histones. Here we describe the clinical, biological, and therapeutic relevance of mutations in epigenetic regulators in AML. In particular, we focus on the role of loss-of-function mutations in TET2, gain-of-function mutations in IDH1 and IDH2, and loss-of-function mutations in ASXL1 and mutations of unclear impact in DNMT3A in AML pathogenesis and therapy. Multiple studies have consistently identified that mutations in these genes have prognostic relevance, particularly in intermediate-risk AML patients, arguing for inclusion of mutational testing of these genetic abnormalities in routine clinical practice. Moreover, biochemical, biological, and epigenomic analyses of the effects of these mutations have informed the development of novel therapies which target pathways deregulated by these mutations. Our understanding of the effects of these mutations on hematopoiesis and potential for therapeutic targeting of specific AML subsets is also reviewed here.
最近对急性髓系白血病（AML）中体细胞遗传改变谱的研究表明，编码在基因转录的表观遗传调控中起重要作用的蛋白质的基因经常发生体细胞突变。这包括涉及 DNA 胞嘧啶残基修饰的蛋白质和催化组蛋白翻译后修饰的酶。在这里，我们描述了 AML 中表观遗传调节剂突变的临床、生物学和治疗相关性。特别是，我们关注 TET2 功能丧失突变、IDH1 和 IDH2 功能获得性突变以及 ASXL1 功能丧失突变和 DNMT3A 中功能不明影响的突变在 AML 发病机制和治疗中的作用。多项研究一致表明，这些基因的突变具有预后相关性，特别是在中危 AML 患者中，这表明在常规临床实践中应包括对这些遗传异常的突变检测。此外，对这些突变影响的生化、生物学和表观基因组学分析为靶向这些突变失调途径的新型治疗方法的发展提供了信息。我们还在这里回顾了这些突变对造血的影响以及针对特定 AML 亚群进行治疗靶向的潜力。
