Figure 1.

IDH pathway and targets in acute leukemia. IDH1/2 catalyze the conversion of isocitrate to α-KG. However, mutations in the catalytic active site of IDH1/2 causes increased affinity to NADPH and α-KG, leading to accumulation of the oncometabolite 2-HG. 2-HG accumulation has several detrimental effects at the cellular level, including hypermethylation of DNA, silencing in cell differentiation pathways (HOX, MAPK, WNT, TGFβ), and impaired metabolic regulation resulting in apoptosis and BCL2 dependence. Specific inhibitors including enasidenib and ivosidenib bind to mIDH1/2 with a greater affinity than isocitrate allowing normal cellular process to continue and decrease the amount of 2-HG production. Other promising agents work on the downstream effects of 2-HG accumulation, including hypomethylating agents (azacitidine and decitabine) restoring cellular differentiation, as well as venetoclax restoring metabolic regulation and apoptotic pathways. Abbreviations: IDH1 = isocitrate dehydrogenase 1, IDH2 = isocitrate dehydrogenase 2, IDH3 = isocitrate dehydrogenase 3, mIDH1 = mutated IDH1, mIDH2 = mutated IDH2, 2-HG = beta-hydroxyglutarate, α-KG = alpha-ketoglutarate, COX = cytochrome c oxidase, Me = methyl group, OH = hydroxyl group, BCL2 = B-cell lymphoma 2, BAX = BCL2 associated protein X, NADP/H = nicotinamide adenine dinucleotide phosphate, NAD/H = nicotinamide adenine dinucleotide.