Department of Pathology, University of Texas Southwestern Medical Center and Children's Medical Center , Dallas, TX , USA ; Department of Pediatrics, University of Texas Southwestern Medical Center and Children's Medical Center , Dallas, TX , USA.
Front Oncol. 2013 Jul 2;3:169. doi: 10.3389/fonc.2013.00169. eCollection 2013.
Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of α-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.
约 20%未经选择的急性髓系白血病 (AML) 病例和 30%细胞遗传学上二倍体的 AML 病例以及 80%的 II-III 级神经胶质瘤和继发性胶质母细胞瘤存在异柠檬酸脱氢酶 (IDH) 1 和 2 基因突变。IDH1/2 突变阻止异柠檬酸的氧化脱羧为 α-酮戊二酸 (α-KG)，并调节 IDH 的功能（新功能），从而促进 α-KG 向 D-2-羟基戊二酸 (D-2HG) 的还原，D-2HG 是一种潜在的致癌代谢物。D-2HG 被认为是 α-KG 依赖性加双氧酶的竞争性抑制剂，包括脯氨酰羟化酶和染色质修饰酶。最终结果是细胞内 DNA 超甲基化的全面增加和细胞表观遗传状态的改变，这被认为在多种肿瘤的发展中起作用。在这篇综述中，我们提供了最新的潜在分子机制的更新，这些机制将 IDH1/2 突变和由此产生的致癌代谢物 D-2HG 与恶性转化联系起来。此外，在 AML 和神经胶质瘤患者中，我们重点关注 IDH1/2 突变与临床、形态学、细胞遗传学和分子特征之间的关联。
