Idle Jeffrey R, Seipel Katja, Bacher Ulrike, Pabst Thomas, Beyoğlu Diren
Arthur G. Zupko's Systems Pharmacology and Pharmacogenomics, Arnold and Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, NY 11201-5423, USA.
Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland.
Cancers (Basel). 2020 Oct 1;12(10):2842. doi: 10.3390/cancers12102842.
Acute myeloid leukemia (AML) frequently harbors mutations in isocitrate 1 () and 2 () genes, leading to the formation of the oncometabolite (2)-hydroxyglutaric acid (2R-HG) with epigenetic consequences for AML proliferation and differentiation. To investigate if broad metabolic aberrations may result from and mutations in AML, plasma metabolomics was conducted by gas chromatography-mass spectrometry (GC-MS) on 51 AML patients, 29 / wild-type (WT), 9 with IDH1R132, 12 with IDH2R140 and one with IDH2R172 mutations. Distinct metabolic differences were observed between IDH1/2 WT, and patients that comprised 22 plasma metabolites that were mainly amino acids. Only two plasma metabolites were statistically significantly different ( 0.0001) between both IDH1R132 and WT and IDH2R140 and WT IDH1/2, specifically (2)-hydroxyglutaric acid (2R-HG) and the threonine metabolite (2,3)-dihydroxybutanoic acid (2,3-DHBA). Moreover, 2R-HG correlated strongly ( 0.0001) with 2,3-DHBA in plasma. One WT patient was discovered to have a D-2-hydroxyglutarate dehydrogenase () A426T inactivating mutation but this had little influence on 2R-HG and 2,3-DHBA plasma concentrations. Expression of transporter genes and 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; 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.
急性髓系白血病（AML）常伴有异柠檬酸脱氢酶1（IDH1）和2（IDH2）基因的突变，导致致癌代谢物（2R）-2-羟基戊二酸（2R-HG）的形成，对AML的增殖和分化产生表观遗传学影响。为了研究AML中IDH1和IDH2突变是否会导致广泛的代谢异常，采用气相色谱-质谱联用（GC-MS）技术对51例AML患者进行了血浆代谢组学分析，其中29例为IDH1/2野生型（WT），9例IDH1 R132突变，12例IDH2 R140突变，1例IDH2 R172突变。在IDH1/2 WT、IDH1突变和IDH2突变患者之间观察到明显的代谢差异，包括22种主要为氨基酸的血浆代谢物。在IDH1 R132与WT、IDH2 R140与WT IDH1/2之间，只有两种血浆代谢物在统计学上有显著差异（P<0.0001），分别为（2R）-2-羟基戊二酸（2R-HG）和苏氨酸代谢物（2,3）-二羟基丁酸（2,3-DHBA）。此外，血浆中2R-HG与2,3-DHBA高度相关（P<0.0001）。发现1例WT患者存在D-2-羟基戊二酸脱氢酶（D2HGDH）A426T失活突变，但这对血浆中2R-HG和2,3-DHBA的浓度影响不大。转运蛋白基因SLC1A5和SLC2A1的表达与血浆中2R-HG浓度呈弱相关，但与2,3-DHBA浓度无关。受试者工作特征（ROC）分析表明，与2R-HG相比，2,3-DHBA是IDH突变更好的生物标志物（曲线下面积（AUC）=0.861；P<0.0001；特异性80%；敏感性87.3%）。研究得出结论，2,3-DHBA和2R-HG均由突变的IDH1 R132、IDH2 R140和IDH2 R172形成，提示2,3-DHBA在AML发病机制中可能发挥作用。
