@article{aca39aefe2ea4aa6a9f6099dce87e0c0,
title = "Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis",
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 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.",
keywords = "DNA (hydroxy)methylation, Wnt, glioma, hydroxyglutarate, hydroxylase, isocitrate dehydrogenase, oncometabolite, stem cell, subventricular zone, α-ketoglutarate",
author = "Chiara Bardella and Osama Al-Dalahmah and Daniel Krell and Pijus Brazauskas and Khalid Al-Qahtani and Marketa Tomkova and Julie Adam and S{\'e}bastien Serres and Helen Lockstone and Luke Freeman-Mills and Inga Pfeffer and Nicola Sibson and Robert Goldin and Benjamin Schuster-B{\"o}eckler and Pollard, {Patrick J.} and Tomoyoshi Soga and McCullagh, {James S.} and Schofield, {Christopher J.} and Paul Mulholland and Olaf Ansorge and Skirmantas Kriaucionis and Ratcliffe, {Peter J.} and Szele, {Francis G.} and Ian Tomlinson",
note = "Funding Information: We acknowledge funding from: Cancer Research UK (grants A12055 and C5255 / A15935 ) to I.T., C.J.S., P.J.R., N.S.; the Wellcome Trust ( 090532/Z/09/Z ) to I.T.; John Fell OUP Research Fund to O.A.; and King Saud University to K.A. Nestin-Cre mice, generated by Fran{\c c}ois Tronche, were provided by Axel Behrens (Cancer Research UK, London Research Institute). Nestin-Cre ER(T2) , originally from the Eisch laboratory, and R26R-EYFP mice were provided by Xin Lu (Ludwig Institute, Oxford). ReNcell CX cells were provided by Eric O'Neill (Oxford Institute for Radiation Oncology). Lentiviral transfer and packaging vectors were from Elisa Vigna (IRCC, Turin). The following gave help and advice: Thomas Cadoux-Hudson, Nick De Pennington, Keith Morris, Wellcome Trust Centre for Human Genetics Genomics and Cellular Imaging Cores, Jerome Nicod, Carme Mont, James Hillis, Bin Sun, Martin Ducker, and Julie Davies. Patrick Pollard died during the preparation of this manuscript. We acknowledge his important contributions to cancer metabolism research. Publisher Copyright: {\textcopyright} 2016 The Authors",
year = "2016",
month = oct,
day = "10",
doi = "10.1016/j.ccell.2016.08.017",
language = "English",
volume = "30",
pages = "578--594",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}
