The emerging role of d-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms

Dinesh Rakheja, L. Jeffrey Medeiros, Scott Bevan, Weina Chen

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Approximately 20% of unselected cases and 30% cytogenetically diploid cases of acute myeloid leukemia (AML) and 80% of grade II-III gliomas and secondary glioblastomas carry mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes. IDH1/2 mutations prevent oxidative decarboxylation of isocitrate to a-ketoglutarate (a-KG) and modulate the function of IDH (neomorphic activity) thereby facilitating reduction of a-KG to D-2-hydroxyglutarate (D-2HG), a putative oncometabolite. D-2HG is thought to act as a competitive inhibitor of α-KG-dependent dioxygenases that include prolyl hydroxylases and chromatin-modifying enzymes. The end result is a global increase of cellular DNA hypermethylation and alterations of the cellular epigenetic state, which has been proposed to play a role in the development of a variety of tumors. In this review, we provide an update on potential molecular mechanisms linking IDH1/2 mutations and the resulting oncometabolite, D-2HG, with malignant transformation. In addition, in patients with AML and glioma we focus on the associations between IDH1/2 mutations and clinical, morphologic, cytogenetic, and molecular characteristics.

Original languageEnglish (US)
Article number00169
JournalFrontiers in Oncology
Volume3 JUL
DOIs
StatePublished - 2013

Fingerprint

Central Nervous System Neoplasms
Isocitrate Dehydrogenase
Mutation
Acute Myeloid Leukemia
Glioma
Prolyl Hydroxylases
Dioxygenases
Decarboxylation
Glioblastoma
Diploidy
Epigenomics
Cytogenetics
Chromatin
alpha-hydroxyglutarate
DNA
Enzymes
Genes
Neoplasms

Keywords

  • Acute myeloid leukemia
  • Glioma
  • IDH mutation
  • NPM1 mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

The emerging role of d-2-hydroxyglutarate as an oncometabolite in hematolymphoid and central nervous system neoplasms. / Rakheja, Dinesh; Jeffrey Medeiros, L.; Bevan, Scott; Chen, Weina.

In: Frontiers in Oncology, Vol. 3 JUL, 00169, 2013.

Research output: Contribution to journalArticle

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