Isocitrate dehydrogenase mutations in myeloid malignancies.
Isocitrate dehydrogenase mutations in myeloid malignancies.
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DOI：
10.1038/leu.2016.275
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发表时间：
2017-02
期刊：
影响因子：
11.4
通讯作者：
Swords R
中科院分区：
文献类型：
--
作者：
Medeiros BC;Fathi AT;DiNardo CD;Pollyea DA;Chan SM;Swords R
参与细胞代谢和表观遗传调控的基因的改变与髓系恶性肿瘤的发病机制有关。在大约20%的急性髓性白血病（AML）成人患者和5%的骨髓增生异常综合征（MDS）成人患者中检测到异柠檬酸脱氢酶（IDH）基因的复发突变。IDH蛋白是参与多种细胞过程的同源二聚体酶，包括对缺氧的适应、组蛋白去甲基化和DNA修饰。IDH 2蛋白位于线粒体中，是三羧酸（也称为“柠檬酸”或Krebs）循环的关键组分。IDH 2和IDH 1（位于细胞质中）蛋白均催化异柠檬酸氧化脱羧为α-酮戊二酸（α-KG）。突变型IDH酶具有新变体活性，并催化α-KG还原为2-羟基戊二酸的（R）对映体，这与DNA和组蛋白超甲基化、基因表达改变和造血祖细胞分化受阻有关。突变IDH（mIDH）的预后意义是有争议的，但似乎受到共突变状态和突变的具体位置（IDH 1-R132、IDH 2-R140、IDH 2-R172）的影响。特异性或间接靶向mIDH的治疗目前正在临床研究中;这些治疗通常耐受性良好，并且当作为单药使用时，在用作一线治疗或复发性或难治性AML或MDS时，在一些mIDH患者中显示出诱导应答的前景。mIDH抑制剂与具有非重叠作用机制的药物组合使用尤其有希望，因为此类方案可解决mIDH骨髓恶性肿瘤中涉及的克隆异质性和多因素致病过程。突变分析的进展使检测更加快速方便，成本更低;这种检测应该成为常规诊断检查的一部分，并在复发时重复进行，以确定可能从针对mIDH的治疗中受益的患者。
Alterations to genes involved in cellular metabolism and epigenetic regulation are implicated in the pathogenesis of myeloid malignancies. Recurring mutations in isocitrate dehydrogenase (IDH) genes are detected in approximately 20% of adult patients with acute myeloid leukemia (AML) and 5% of adults with myelodysplastic syndromes (MDS). IDH proteins are homodimeric enzymes involved in diverse cellular processes, including adaptation to hypoxia, histone demethylation and DNA modification. The IDH2 protein is localized in the mitochondria and is a critical component of the tricarboxylic acid (also called the ‘citric acid' or Krebs) cycle. Both IDH2 and IDH1 (localized in the cytoplasm) proteins catalyze the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG). Mutant IDH enzymes have neomorphic activity and catalyze reduction of α-KG to the (R) enantiomer of 2-hydroxyglutarate, which is associated with DNA and histone hypermethylation, altered gene expression and blocked differentiation of hematopoietic progenitor cells. The prognostic significance of mutant IDH (mIDH) is controversial but appears to be influenced by co-mutational status and the specific location of the mutation (IDH1-R132, IDH2-R140, IDH2-R172). Treatments specifically or indirectly targeted to mIDH are currently under clinical investigation; these therapies have been generally well tolerated and, when used as single agents, have shown promise for inducing responses in some mIDH patients when used as first-line treatment or in relapsed or refractory AML or MDS. Use of mIDH inhibitors in combination with drugs with non-overlapping mechanisms of action is especially promising, as such regimens may address the clonal heterogeneity and the multifactorial pathogenic processes involved in mIDH myeloid malignancies. Advances in mutational analysis have made testing more rapid and convenient, and less expensive; such testing should become part of routine diagnostic workup and repeated at relapse to identify patients who may benefit from treatments that target mIDH.