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

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.

Addition of grapes to both a standard and a high-fat Western pattern diet modifies hepatic and urinary metabolite profiles in the mouse

“…2) as described. [25][26][27][28] A principal components analysis (PCA) scores plot showing clustering of the QC sample scores is shown in Supplementary Fig. S1.…”

A Metabolomic Analysis of Cirrhotic Ascites

“…Firstly, the hotspots for serum creatinine concentration (crtn) with 2,3-dihydroxybutanoic acid (2,3-D) in both postoperative drainage fluid and ascites fluid may be related to their respective renal handling. This latter compound is the (2R,3S)-dihydroxybutanoic acid diastereomer, a metabolite of threonine and a putative oncometabolite in acute myeloid leukemia [13,46]. Its water solubility has been estimated as 454 g/L using artificial neural networks [47], considerably greater than creatinine water solubility (90 g/L).…”

Metabolic Rewiring and the Characterization of Oncometabolites

“…It has been proposed that 2,3-DHBA is synthesized by mutant IDH1 and IDH2 similarly to the synthesis of 2R-HG from 2-OG. Moreover, we have also suggested that the precursor of 2,3-DHBA in this reaction is (3S)-hydroxy-2-oxobutanoate formed by the transamination of the amino acid L-threonine (Figure 3) [33]. The properties of 2,3-DHBA with respect to cancer cell proliferation and its epigenetic regulation are yet to be established.…”

“…The current NIST/EPA/NIH EI-MS library contains over 350,000 spectra. We adopted a GC-MS metabolomic workflow to interrogate the small intermediary metabolite component of the plasma [29][30][31][32][33], urine [30], liver [31,34] and cultured cell [35,36] metabolomes. Others have utilized gas chromatography coupled to a time-of-flight mass spectrometer (GC-TOFMS) in cancer research [37].…”

“…Unexpectedly, another plasma metabolite, 2,3-DHBA, was similarly elevated and highly correlated with plasma 2-HG levels. When ROC analysis was conducted, 2,3-DHBA was a superior biomarker (80% specificity; 87.3% sensitivity) for IDH1/2 mutation in AML compared to the oncometabolite 2-HG (80% specificity; 63.8% sensitivity) [33].…”