Abstract
SummaryIsocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H 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. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
Highlights
Gliomas are the most frequent primary brain tumor
The YFP+ cells were expanded in the rostral migratory stream (RMS) of mutant animals, we did not find that the glial tubes were altered in morphology in mutant mice compared with controls. This suggests that the emigration/infiltration of the neuroblast progenitors, as well as the glial progenitors, into the regions adjacent to RMS and subventricular zone (SVZ) is probably cell autonomous. These results suggest that expression of Idh1R132H in adult mouse stem/progenitor cells robustly induced expansion of the SVZ and RMS and infiltration into adjacent regions, similar to observations of glioma cell invasion
We found no clear evidence that collagen-prolyl hydroxylases (PHDs), reactive oxygen species (ROS), HIFPHDs, or JmjC domain histone demethylases (JHDMs) were altered in the Tam-Idh1-KI mice (Figures S5B–S5F, Table S1)
Summary
Gliomas are the most frequent primary brain tumor. They have diverse morphology, genetic status, and response to therapy.Grade I gliomas are characterized by slow growth. Gliomas are the most frequent primary brain tumor. They have diverse morphology, genetic status, and response to therapy. Grade I gliomas are characterized by slow growth. Glioblastoma (grade IV, GBM), the most common and most aggressive glioma, may develop rapidly without Significance. IDH1R132H is a driver mutation in gliomas and other malignancies, probably causing tumorigenesis through D-2-hydroxyglutarate accumulation, the downstream mechanisms remain unclear. We found that adult mice expressing Idh1R132H in the brain subventricular zone (SVZ) develop features of gliomagenesis, including increased numbers of neural stem cells and their progeny. The gene expression profile of the Idh1R132H SVZ closely overlaps those of human gliomas. Non-exclusive tumorigenic mechanisms included promotion of a neural stem cell phenotype, Wnt pathway activation, maintenance of telomeres, and DNA hypermethylation. Our Idh1R132H mouse provides a system for assessing brain tumor therapies in vivo
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