Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 110; no. 42; pp. 17017 - 17022
• Main Authors: Wang, Jiang-Han, Chen, Wen-Lian, Li, Jun-Min, Wu, Song-Fang, Chen, Tian-Lu, Zhu, Yong-Mei, Zhang, Wei-Na, Li, Yang, Qiu, Yun-Ping, Zhao, Ai-Hua, Mi, Jian-Qing, Jin, Jie, Wang, Yun-Gui, Ma, Qiu-Ling, Huang, He, Wu, De-Pei, Wang, Qin-Rong, Li, Yan, Yan, Xiao-Jing, Yan, Jin-Song, Li, Jian-Yong, Wang, Shuai, Huang, Xiao-Jun, Wang, Bing-Shun, Jia, Wei, Shen, Yang, Chen, Zhu, Chen, Sai-Juan
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15.10.2013; NATIONAL ACADEMY OF SCIENCES; National Acad Sciences
• Subjects: Biological Sciences; Blasts; blood serum; China; China - epidemiology; Cytogenetics; Disease-Free Survival; DNA; DNA methylation; DNA Methylation - genetics; Enzymes; Female; Gene Expression Regulation, Leukemic - genetics; genes; Genetic mutation; Glutarates - blood; Hematology; Humans; isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Leukemia; Leukemia, Myeloid, Acute - blood; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - therapy; Lymphoma; Male; Mass spectrometry; Medical prognosis; Metabolites; Methylation; Middle Aged; multivariate analysis; Mutation; Myeloid leukemia; P values; patients; Statistical median; Survival Rate; China; biomarker; prognosis
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1315558110

The 2-hydroxyglutarate (2-HG) has been reported to result from mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes and to function as an “oncometabolite.” To evaluate the clinical significance of serum 2-HG levels in hematologic malignancies, acute myeloid leukemia (AML) in particular, we analyzed this metabolite in distinct types of human leukemia and lymphoma and established the range of serum 2-HG in appropriate normal control individuals by using gas chromatograph–time-of-flight mass spectrometry. Aberrant serum 2-HG pattern was detected in the multicenter group of AML, with 62 of 367 (17%) patients having 2-HG levels above the cutoff value (2.01, log ₂-transformed from 4.03 μg/mL). IDH1/2 mutations occurred in 27 of 31 (87%) AML cases with very high 2-HG, but were observed only in 9 of 31 (29%) patients with moderately high 2-HG, suggesting other genetic or biochemical events may exist in causing 2-HG elevation. Indeed, glutamine-related metabolites exhibited a pattern in favor of 2-HG synthesis in the high 2-HG group. In AML patients with cytogenetically normal AML (n = 234), high 2-HG represented a negative prognostic factor in both overall survival and event-free survival. Univariate and multivariate analyses confirmed high serum 2-HG as a strong prognostic predictor independent of other clinical and molecular features. We also demonstrated distinct gene-expression/DNA methylation profiles in AML blasts with high 2-HG compared with those with normal ones, supporting a role that 2-HG plays in leukemogenesis.