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

Jiang-Han Wang, Wen-Lian Chen, Jun-Min Li, Song-Fang Wu, Tian-Lu Chen, Yong-Mei Zhu, Wei-Na Zhang, Yang Li, Yun-Ping Qiu, Ai-Hua Zhao, Jian-Qing Mi, Jie Jin, Yun-Gui Wang, Qiu-Ling Ma, He Huang, De-Pei Wu, Qin-Rong Wang, Yan Li, Xiao-Jing Yan, Jin-Song Yan, Jian-Yong Li, Shuai Wang, Xiao-Jun Huang, Bing-Shun Wang, Wei Jia, Yang Shen, Zhu Chen, Sai-Juan Chen

Index: Proc. Natl. Acad. Sci. U. S. A. 110(42) , 17017-22, (2013)

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Abstract

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, log2-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.