Abstract
Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1(R132H) in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1(R132H) mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
Original language | English |
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Pages (from-to) | 578-594 |
Number of pages | 17 |
Journal | Cancer Cell |
Volume | 30 |
Issue number | 4 |
Early online date | 29 Sept 2016 |
DOIs | |
Publication status | Published - 10 Oct 2016 |
Keywords
- Animals
- Brain Neoplasms
- DNA Methylation
- Glioma
- Isocitrate Dehydrogenase
- Lateral Ventricles
- Mice
- Mice, Transgenic
- Mutation
- Neoplastic Stem Cells
- Stem Cell Niche
- Transcriptome
- Journal Article