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09:43
Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation
Published on: January 14, 2014
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Lenny Dang1, David W White, Stefan Gross
1Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
Nature
|November 26, 2009
Summary
Mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) create a new enzyme function. This function produces R(-)-2-hydroxyglutarate (2HG), an onco-metabolite that drives brain cancer formation and progression.
Area of Science:
- Biochemistry
- Oncology
- Molecular Biology
Background:
- Mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) are prevalent in primary human brain cancers.
- These mutations affect a single amino acid residue in the IDH1 active site, impacting its catalytic function.
Purpose of the Study:
- To investigate the functional consequences of cancer-associated IDH1 mutations.
- To determine if IDH1 mutations confer novel enzymatic activities relevant to gliomagenesis.
Main Methods:
- Enzyme activity assays to assess substrate conversion.
- Structural studies of mutated IDH1 to elucidate mechanism.
- Measurement of R(-)-2-hydroxyglutarate (2HG) levels in human gliomas.
Main Results:
- Cancer-associated IDH1 mutations result in a neomorphic enzymatic activity: the NADPH-dependent reduction of alpha-ketoglutarate to R(-)-2-hydroxyglutarate (2HG).
- Structural analysis reveals active site alterations in mutated IDH1, explaining the shift from oxidative decarboxylation to reductive synthesis.
- Elevated 2HG levels were observed in human malignant gliomas with IDH1 mutations.
Conclusions:
- IDH1 mutations in gliomas lead to the production of the oncometabolite 2HG.
- Accumulation of 2HG contributes to the initiation and malignant progression of gliomas.
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