Section of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy -
Section of Hematology and Clinical Immunology, Department of Medicine, University of Perugia, Perugia, Italy.
Minerva Med. 2020 Oct;111(5):411-426. doi: 10.23736/S0026-4806.20.07024-X. Epub 2020 Sep 21.
The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria, respectively, and contribute to generating the dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as reductive potential in different cellular processes. Mutations in IDH1 and IDH2 genes are found collectively in about 20-25% of acute myeloid leukemia (AML) patients. Mutant IDH enzymes have neomorphic activity and convert αKG to the oncometabolite R-2-hydroxyglutarate (R-2-HG) which accumulates at high levels in the cell and hampers the function of αKG-dependent enzymes, including epigenetic regulators, thus leading to altered gene expression and block of differentiation and contributing to leukemia development. Inhibition of the neomorphic mutants induces marked decrease in R-2-HG levels and restores myeloid differentiation. Enasidenib and ivosidenib are potent and selective inhibitors of mutant IDH2 and IDH1, respectively, act as differentiating agents and showed clinical activity in relapsed/refractory (R/R) AML harboring the specific mutation. As single agents, both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of R/R AML. The relevance of IDH targeting within either single agent approach or, most importantly, combinatorial treatments in AML will be discussed.
异柠檬酸脱氢酶（IDH）酶，IDH1 和 IDH2，分别在细胞质和线粒体中催化异柠檬酸转化为α-酮戊二酸（αKG），并有助于在不同的细胞过程中产生还原电势的二氢烟酰胺腺嘌呤二核苷酸磷酸（NADPH）。IDH1 和 IDH2 基因的突变在大约 20-25%的急性髓系白血病（AML）患者中共同发现。突变的 IDH 酶具有新的酶活性，将αKG 转化为致癌代谢物 R-2-羟基戊二酸（R-2-HG），其在细胞中积累到高水平，抑制αKG 依赖性酶的功能，包括表观遗传调节剂，从而导致基因表达改变和分化阻滞，并有助于白血病的发展。新表型突变体的抑制导致 R-2-HG 水平的显著降低，并恢复髓系分化。Enasidenib 和ivosidenib 分别是突变 IDH2 和 IDH1 的有效且选择性抑制剂，作为分化剂，在携带特定突变的复发性/难治性（R/R）AML 中显示出临床活性。作为单一药物，这两种药物均已被美国食品和药物管理局（FDA）批准用于治疗 R/R AML。将讨论在 AML 中，无论是单一药物方法还是更重要的联合治疗中，IDH 靶向的相关性。
