IDH mutations in acute myeloid leukemia
IDH mutations in acute myeloid leukemia
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DOI：
10.1016/j.humpath.2012.05.003
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发表时间：
2012-10-01
期刊：
影响因子：
3.3
通讯作者：
Chen, Weina
中科院分区：
文献类型：
--
作者：
Rakheja, Dinesh;Konoplev, Sergej;Chen, Weina
急性髓系白血病是一组异质性疾病。异柠檬酸脱氢酶（IDH）基因突变是急性髓细胞白血病中一类新的点突变。这些突变阻止异柠檬酸氧化脱羧为α-酮戊二酸，并赋予新的酶活性，促进α-酮戊二酸还原为D-2-羟基戊二酸（一种推定的致癌代谢物）。IDH 1/IDH 2突变是杂合的，并且它们的组合频率在急性髓性白血病病例中约为17%，在细胞遗传学正常的急性髓性白血病病例中为27%，并且在具有杯状核的急性髓性白血病病例中高达67%。这些突变在很大程度上是相互排斥的。尽管IDH 1和IDH 2突变有许多相似之处，但它们可能代表急性骨髓性白血病的不同分子或临床亚组。所有已知的突变涉及IDH 1的密码子132或IDH 2的密码子140或172中的精氨酸（R）。IDH 1（R132）和IDH 2（R140）突变通常伴随正常细胞遗传学和NPM 1突变，而IDH 2（R172）通常是在急性髓性白血病中检测到的唯一突变。越来越多的证据表明IDH 1/2突变的预后影响根据特定突变而变化，并且还取决于其他基因的并发突变的背景。IDH 1（R132）突变可能预测分子低风险急性髓性白血病患者的预后不良，而IDH 2（R172）突变则导致急性髓性白血病患者预后不良。IDH 1/2突变体的表达诱导整体DNA超甲基化的增加，并抑制TET 2诱导的胞嘧啶5-羟甲基化和DNA去甲基化。这些数据表明，IDH 1/2突变构成了急性髓性白血病中的一个独特的突变类别，其影响表观遗传状态，这是开发治疗剂的重要考虑因素。(C)2012 Elsevier Inc. All rights reserved.
Acute myeloid leukemia is a heterogeneous group of diseases. Mutations of the isocitrate dehydrogenase (IDH) genes represent a novel class of point mutations in acute myeloid leukemia. These mutations prevent oxidative decarboxylation of isocitrate to a-ketoglutarate and confer novel enzymatic activity, facilitating the reduction of a-ketoglutarate to D-2-hydroxyglutarate, a putative oncometabolite. IDH1/IDH2 mutations are heterozygous, and their combined frequency is approximately 17% in unselected acute myeloid leukemia cases, 27% in cytogenetically normal acute myeloid leukemia cases, and up to 67% in acute myeloid leukemia cases with cuplike nuclei. These mutations are largely mutually exclusive. Despite many similarities of IDH1 and IDH2 mutations, it is possible that they represent distinct molecular or clinical subgroups of acute myeloid leukemia. All known mutations involve arginine (R), in codon 132 of IDH1 or codon 140 or 172 of IDH2. IDH1(R132) and IDH2(R140) mutations are frequently accompanied by normal cytogeneties and NPM1 mutation, whereas IDH2(R172) is frequently the only mutation detected in acute myeloid leukemia. There is increasing evidence that the prognostic impact of IDH1/2 mutations varies according to the specific mutation and also depends on the context of concurrent mutations of other genes. IDH1(R132) mutation may predict poor outcome in a subset of patients with molecular low-risk acute myeloid leukemia, whereas IDH2(R172) mutations confer a poor prognosis in patients with acute myeloid leukemia. Expression of IDH1/2 mutants induces an increase in global DNA hypermethylation and inhibits TET2-induced cytosine 5-hydroxymethylation, DNA demethylation. These data suggest that IDH1/2 mutations constitute a distinct mutational class in acute myeloid leukemia, which affects the epigenetic state, an important consideration for the development of therapeutic agents. (C) 2012 Elsevier Inc. All rights reserved.