(2R,3S)-Dihydroxybutanoic Acid Synthesis as a Novel Metabolic Function of Mutant Isocitrate Dehydrogenase 1 and 2 in Acute Myeloid Leukemia

SIMPLE SUMMARY: Acute myeloid leukemia (AML) is one of several cancers where cancer proliferation occurs under the influence of an aberrant metabolite known as an oncometabolite produced by a mutated enzyme in the cancer cell. In AML, mutant isocitrate dehydrogenases produce the oncometabolite 2-hydroxyglutarate. We screened AML patients with and without mutant isocitrate dehydrogenases by using a technique known as metabolomics, which measures many different metabolites in patient plasma. It was observed that another metabolite, 2,3-dihydroxybutyrate, was produced in larger amounts in patients with mutated isocitrate dehydrogenase and correlated strongly with 2-hydroxyglutarate levels. Moreover, 2,3-dihydroxybutyrate was a better indicator of the presence of mutated isocitrate dehydrogenase in the cancer than the known oncometabolite 2-hydroxyglutarate. These findings may lead to the characterization of 2,3-dihydroxybutyrate as a novel oncometabolite in AML, which would bring a fuller understanding of the etiology of this disease and offer opportunities for the development of novel therapeutic agents. ABSTRACT: Acute myeloid leukemia (AML) frequently harbors mutations in isocitrate 1 (IDH1) and 2 (IDH2) genes, leading to the formation of the oncometabolite (2R)-hydroxyglutaric acid (2R-HG) with epigenetic consequences for AML proliferation and differentiation. To investigate if broad metabolic aberrations may result from IDH1 and IDH2 mutations in AML, plasma metabolomics was conducted by gas chromatography–mass spectrometry (GC–MS) on 51 AML patients, 29 IDH1/2 wild-type (WT), 9 with IDH1R132, 12 with IDH2R140 and one with IDH2R172 mutations. Distinct metabolic differences were observed between IDH1/2 WT, IDH1R132 and IDH2R140 patients that comprised 22 plasma metabolites that were mainly amino acids. Only two plasma metabolites were statistically significantly different (p < 0.0001) between both IDH1R132 and WT IDH1/2 and IDH2R140 and WT IDH1/2, specifically (2R)-hydroxyglutaric acid (2R-HG) and the threonine metabolite (2R,3S)-dihydroxybutanoic acid (2,3-DHBA). Moreover, 2R-HG correlated strongly (p < 0.0001) with 2,3-DHBA in plasma. One WT patient was discovered to have a D-2-hydroxyglutarate dehydrogenase (D2HGDH) A426T inactivating mutation but this had little influence on 2R-HG and 2,3-DHBA plasma concentrations. Expression of transporter genes SLC16A1 and SLC16A3 displayed a weak correlation with 2R-HG but not 2,3-DHBA plasma concentrations. Receiver operating characteristic (ROC) analysis demonstrated that 2,3-DHBA was a better biomarker for IDH mutation than 2R-HG (Area under the curve (AUC) 0.861; p < 0.0001; 80% specificity; 87.3% sensitivity). It was concluded that 2,3-DHBA and 2R-HG are both formed by mutant IDH1R132, IDH2R140 and IDH2R172, suggesting a potential role of 2,3-DHBA in AML pathogenesis.