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

Jiang Han Wang, Wen Lian Chen, Jun Min Li, Yan 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, Xiao Jing Yan, Jin Song YanJian Yong Li, Shuai Wang, Xiao Jun Huang, Bing Shun Wang, Wei Jia, Yang Shen, Zhu Chen, Sai Juan Chen

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66 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)17017-17022
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number42
DOIs
StatePublished - Oct 15 2013

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Keywords

  • Biomarker
  • Prognosis

ASJC Scopus subject areas

  • General

Cite this

Wang, J. H., Chen, W. L., Li, J. M., Li, Y., Wu, S. F., Chen, T. L., Zhu, Y. M., Zhang, W. N., Li, Y., Qiu, Y. P., Zhao, A. H., Mi, J. Q., Jin, J., Wang, Y. G., Ma, Q. L., Huang, H., Wu, D. P., Wang, Q. R., Yan, X. J., ... Chen, S. J. (2013). Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China. Proceedings of the National Academy of Sciences of the United States of America, 110(42), 17017-17022. https://doi.org/10.1073/pnas.1315558110