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

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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number1
DOIs
StatePublished - Jan 11 2018

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Plasma Cells
Glutamine
Disease Progression
Multiple Myeloma
Neoplasms
Metabolomics
Isotopes
Glucose
Cell Line
alpha-hydroxyglutarate

Keywords

  • Cancer
  • Hematology
  • Oncology

Cite this

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

In: JCI insight, Vol. 3, No. 1, 11.01.2018.

Research output: Contribution to journalArticle

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