Department of Pathology, The University of Texas Southwestern Medical Center and Children's Medical Center, Dallas, TX, USA.
Hum Pathol. 2012 Oct;43(10):1541-51. doi: 10.1016/j.humpath.2012.05.003. Epub 2012 Aug 20.
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 α-ketoglutarate and confer novel enzymatic activity, facilitating the reduction of α-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 cytogenetics 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.
急性髓系白血病是一组异质性疾病。异柠檬酸脱氢酶（IDH）基因突变代表急性髓系白血病中一类新的点突变。这些突变阻止异柠檬酸的氧化脱羧作用生成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，这是一种潜在的致癌代谢物。IDH1/IDH2 突变是杂合的，在未经选择的急性髓系白血病病例中，其合并频率约为 17%，在核型正常的急性髓系白血病病例中为 27%，在具有杯状核的急性髓系白血病病例中高达 67%。这些突变基本上是互斥的。尽管 IDH1 和 IDH2 突变有许多相似之处，但它们可能代表急性髓系白血病的不同分子或临床亚组。所有已知的突变都涉及精氨酸（R），位于 IDH1 的 132 位密码子或 IDH2 的 140 位或 172 位密码子。IDH1（R132）和 IDH2（R140）突变常伴有正常核型和 NPM1 突变，而 IDH2（R172）突变常是急性髓系白血病中唯一检测到的突变。越来越多的证据表明，IDH1/2 突变的预后影响因具体突变而异，也取决于其他基因的并发突变的情况。IDH1（R132）突变可能预示着部分分子低危急性髓系白血病患者的不良预后，而 IDH2（R172）突变则预示着急性髓系白血病患者的不良预后。IDH1/2 突变体的表达诱导全基因组 DNA 超甲基化增加，并抑制 TET2 诱导的胞嘧啶 5-羟甲基化，即 DNA 去甲基化。这些数据表明，IDH1/2 突变构成了急性髓系白血病中一个独特的突变类别，影响表观遗传状态，这是开发治疗药物的一个重要考虑因素。
