Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies
Wilson I. Gonsalves, Vijay Ramakrishnan, Taro Hitosugi, Toshi Ghosh, Dragan Jevremovic, Tumpa Dutta, Dhananjay Sakrikar, Xuan-Mai Petterson, Linda Wellik, Shaji K. Kumar, K. Sreekumaran Nair
Wilson I. Gonsalves, Vijay Ramakrishnan, Taro Hitosugi, Toshi Ghosh, Dragan Jevremovic, Tumpa Dutta, Dhananjay Sakrikar, Xuan-Mai Petterson, Linda Wellik, Shaji K. Kumar, K. Sreekumaran Nair
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Research Article Hematology Oncology

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

Abstract

The production of the oncometabolite 2-hydroxyglutarate (2-HG) has been associated with c-MYC overexpression. c-MYC also regulates glutamine metabolism and drives progression of asymptomatic precursor plasma cell (PC) malignancies to symptomatic multiple myeloma (MM). However, the presence of 2-HG and its clinical significance in PC malignancies is unknown. By performing 13C stable isotope resolved metabolomics (SIRM) using U[13C6]Glucose and U[13C5]Glutamine in human myeloma cell lines (HMCLs), we show that 2-HG is produced in clonal PCs and is derived predominantly from glutamine anaplerosis into the TCA cycle. Furthermore, the 13C SIRM studies in HMCLs also demonstrate that glutamine is preferentially utilized by the TCA cycle compared with glucose. Finally, measuring the levels of 2-HG in the BM supernatant and peripheral blood plasma from patients with precursor PC malignancies such as smoldering MM (SMM) demonstrates that relatively elevated levels of 2-HG are associated with higher levels of c-MYC expression in the BM clonal PCs and with a subsequent shorter time to progression (TTP) to MM. Thus, measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM patients offers potential early identification of those patients at high risk of progression to MM, who could benefit from early therapeutic intervention.

Authors

Wilson I. Gonsalves, Vijay Ramakrishnan, Taro Hitosugi, Toshi Ghosh, Dragan Jevremovic, Tumpa Dutta, Dhananjay Sakrikar, Xuan-Mai Petterson, Linda Wellik, Shaji K. Kumar, K. Sreekumaran Nair

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Figure 7

2-HG levels in the BM supernatant predicts for shorter time to progression of smoldering multiple myeloma to multiple myeloma.

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2-HG levels in the BM supernatant predicts for shorter time to progressi...
(A) Kaplan-Meier curve showing the time to progression (TTP) of patients with smoldering multiple myeloma (SMM) with a 2-hydroxyglutarate (2-HG) level in the BM supernatant higher than the median 2-HG level (elevated 2-HG) (n = 10) compared with patients with SM) with a 2-HG level in the BM supernatant lower or equal to the median 2-HG levels of the cohort (nonelevated 2-HG) (n = 15). Comparisons were made by the Wilcoxon test, and significance was defined as P < 0.05. (B) Bar graph representing the percentage of SMM patients with 2-HG levels in the BM supernatant higher than the median 2-HG level (elevated 2-HG) (n = 10) or lower than the median 2-HG level (nonelevated 2-HG) (n = 15) who progressed to MM in 1 year from the time of 2-HG level assessment. Comparisons were made by the 2-tailed Fisher’s exact test, and significance was defined as P < 0.05. (C) Dot plot graph depicting the individual (red circles and blue squares), mean (red and blue line), and ± SEM (black error bars) of 2-HG concentrations in the BM supernatant of patients with SMM who progressed to MM within 12 months or less (n = 13) and later than 12 months (n = 12). Comparisons were made by the Mann-Whitney test, and significance was defined as P < 0.05.