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

TitlePrognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China.
Publication TypeJournal Article
Year of Publication2013
AuthorsWang J-H, Chen W-L, Li J-M, 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, Li Y, Yan X-J, Yan J-S, Li J-Y, Wang S, Huang X-J, Wang B-S, Jia W, Shen Y, Chen Z, Chen S-J
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue42
Pagination17017-22
Date Published2013 Oct 15
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.

DOI10.1371/journal.pone.0076036
Alternate JournalProc. Natl. Acad. Sci. U.S.A.