文章：

表观遗传调控因子突变在髓系恶性肿瘤中的作用

The role of mutations in epigenetic regulators in myeloid malignancies

原文发布日期：2012-08-17

DOI: 10.1038/nrc3343

类型: Review Article

开放获取: 否

要点：

1. Mutations in epigenetic modifiers account for new classes of mutant disease alleles that contribute to the pathogenesis of myeloid malignancies in addition to the classical class I genes that affect proliferation and class II genes that affect differentiation.
2. Mutations in isocitrate dehydrogenase 1 (IDH1), IDH2 or tet methylcytosine dioxygenase 2 (TET2) affect 5-hydroxymethylcytosine modification of DNA, which alters methylation and haematopoietic development.
3. Mutations and translocations involving mixed-lineage leukaemia (MLL) as well as mutations in Polycomb repressive complex (PRC) components and interacting proteins affect histone modifications and can promote myeloid transformation.
4. Previously identified mutations, such as janus kinase 2 (JAK2)-V617F and fusion proteins involving translocation of the promyelocytic leukaemia (PML) gene, also contribute to epigenetic modifications in myeloid malignancies.
5. Epigenetic mutations are modifications that are reversible with therapy. Mutations in enzymatic modifiers represent attractive targets for directed therapy in myeloid malignancies.

要点翻译：

1. 表现遗传修饰因子的突变构成了新的疾病等位基因突变类型，这些突变与影响增殖的经典I类基因和影响分化的II类基因共同促进髓系恶性肿瘤的发病机制。
2. 异柠檬酸脱氢酶1（IDH1）、IDH2或Tet甲基胞嘧啶双加氧酶2（TET2）的突变会影响DNA的5-羟甲基胞嘧啶修饰，从而改变甲基化状态和造血发育进程。
3. 涉及混合谱系白血病（MLL）的突变与易位，以及Polycomb抑制复合物（PRC）组分及其相互作用蛋白的突变，会影响组蛋白修饰并可能促进髓系转化。
4. 先前发现的突变，如Janus激酶2（JAK2）-V617F和涉及早幼粒细胞白血病（PML）基因易位的融合蛋白，同样参与髓系恶性肿瘤的表现遗传修饰。
5. 表现遗传突变具有可通过治疗逆转的特性。酶类修饰因子的突变成为髓系恶性肿瘤靶向治疗极具吸引力的干预靶点。

英文摘要：

Recent genomic studies have identified novel recurrent somatic mutations in patients with myeloid malignancies, including myeloproliferative neoplasms (MPNs), myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). In some cases these mutations occur in genes with known roles in regulating chromatin and/or methylation states in haematopoietic progenitors, and in other cases genetic and functional studies have elucidated a role for specific mutations in altering epigenetic patterning in myeloid malignancies. In this Review we discuss recent genetic and functional data implicating mutations in epigenetic modifiers, including tet methylcytosine dioxygenase 2 (TET2), isocitrate dehydrogenase 1 (IDH1), IDH2, additional sex combs-like 1 (ASXL1), enhancer of zeste homologue 2 (EZH2) and DNA methyltransferase 3A (DNMT3A), in the pathogenesis of MPN, MDS and AML, and discuss how this knowledge is leading to novel clinical, biological and therapeutic insights.

摘要翻译： 

近期基因组学研究在骨髓增殖性肿瘤（MPN）、骨髓增生异常综合征（MDS）和急性髓系白血病（AML）等髓系恶性肿瘤患者中发现了新的复发性体细胞突变。其中部分突变发生在已知具有调控造血祖细胞染色质和/或甲基化状态的基因中；另一些突变则通过遗传学和功能研究被证实能够改变髓系恶性肿瘤的表观遗传模式。本文综述了近期遗传学和功能数据，揭示表观遗传调控因子——包括TET2、IDH1、IDH2、ASXL1、EZH2和DNMT3A等基因的突变——在MPN、MDS及AML发病机制中的作用，并探讨这些发现如何推动新的临床、生物学及治疗学见解的产生。

原文链接：

The role of mutations in epigenetic regulators in myeloid malignancies