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Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis

Bardella, Chiara; Al-Dalahmah, Osama; Krell, Daniel; Brazauskas, Pijus; Al-Qahtani, Khalid; Tomkova, Marketa; Adam, Julie; Serres, Sebastien; Lockstone, Helen; Freeman-Mills, Luke; Pfeffer, Inga; Sibson, Nicola; Goldin, Robert; Schuster-B�eckler, Benjamin; Pollard, Patrick J.; Soga, Tomoyoshi; McCullagh, James S.; Schofield, Christopher J.; Mulholland, Paul; Ansorge, Olaf; Kriaucionis, Skirmantas; Ratcliffe, Peter J.; Szele, Francis G.; Tomlinson, Ian

Authors

Chiara Bardella

Osama Al-Dalahmah

Daniel Krell

Pijus Brazauskas

Khalid Al-Qahtani

Marketa Tomkova

Julie Adam

SEBASTIEN SERRES Sebastien.Serres@nottingham.ac.uk
Assistant Professor in Metabolic Biochemistry

Helen Lockstone

Luke Freeman-Mills

Inga Pfeffer

Nicola Sibson

Robert Goldin

Benjamin Schuster-B�eckler

Patrick J. Pollard

Tomoyoshi Soga

James S. McCullagh

Christopher J. Schofield

Paul Mulholland

Olaf Ansorge

Skirmantas Kriaucionis

Peter J. Ratcliffe

Francis G. Szele

Ian Tomlinson



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 ?-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.

Citation

Bardella, C., Al-Dalahmah, O., Krell, D., Brazauskas, P., Al-Qahtani, K., Tomkova, M., …Tomlinson, I. (2016). Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer Cell, 30(4), 578-594. https://doi.org/10.1016/j.ccell.2016.08.017

Journal Article Type Article
Acceptance Date Aug 29, 2016
Online Publication Date Sep 29, 2016
Publication Date Oct 10, 2016
Deposit Date Mar 8, 2017
Publicly Available Date Mar 28, 2024
Journal Cancer Cell
Print ISSN 1535-6108
Electronic ISSN 1878-3686
Publisher Elsevier (Cell Press)
Peer Reviewed Peer Reviewed
Volume 30
Issue 4
Pages 578-594
DOI https://doi.org/10.1016/j.ccell.2016.08.017
Public URL http://www.ncbi.nlm.nih.gov/pubmed/27693047
Publisher URL https://www.sciencedirect.com/science/article/pii/S1535610816304020?via%3Dihub
Additional Information This article is maintained by: Elsevier; Article Title: Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis; Journal Title: Cancer Cell; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ccell.2016.08.017; Content Type: article; Copyright: © 2016 The Author(s). Published by Elsevier Inc.

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