Expression of Idh1(R132H) in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis

Chiara Bardella; Osama Al-Dalahmah; Daniel Krell; Pijus Brazauskas; Khalid Al-Qahtani; Marketa Tomkova; Julie Adam; Sébastien Serres; Helen Lockstone; Luke Freeman-Mills; Inga Pfeffer; Nicola Sibson; Robert Goldin; Benjamin Schuster-Böeckler; 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; Ian Tomlinson

doi:10.1016/j.ccell.2016.08.017

Expression of Idh1(R132H) in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis

Chiara Bardella
, Osama Al-Dalahmah
, Daniel Krell
, Pijus Brazauskas
, Khalid Al-Qahtani
, Marketa Tomkova
, Julie Adam
, Sébastien Serres
, Helen Lockstone
, Luke Freeman-Mills
, Inga Pfeffer
, Nicola Sibson
, Robert Goldin
, Benjamin Schuster-Böeckler
, 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, Ian Tomlinson

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

66 Citations (Scopus)

238 Downloads (Pure)

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
Pages (from-to)	578-594
Number of pages	17
Journal	Cancer Cell
Volume	30
Issue number	4
Early online date	29 Sept 2016
DOIs	https://doi.org/10.1016/j.ccell.2016.08.017
Publication status	Published - 10 Oct 2016

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Animals
Brain Neoplasms
DNA Methylation
Glioma
Isocitrate Dehydrogenase
Lateral Ventricles
Mice
Mice, Transgenic
Mutation
Neoplastic Stem Cells
Stem Cell Niche
Transcriptome
Journal Article

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Bardella, C., Al-Dalahmah, O., Krell, D., Brazauskas, P., Al-Qahtani, K., Tomkova, M., Adam, J., Serres, S., Lockstone, H., Freeman-Mills, L., Pfeffer, I., Sibson, N., Goldin, R., Schuster-Böeckler, B., Pollard, P. J., Soga, T., McCullagh, J. S., Schofield, C. J., Mulholland, P., ... Tomlinson, I. (2016). Expression of Idh1(R132H) 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

@article{67eb75b28ad54f6d8492e7e2549484c1,

title = "Expression of Idh1(R132H) 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 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.",

keywords = "Animals, Brain Neoplasms, DNA Methylation, Glioma, Isocitrate Dehydrogenase, Lateral Ventricles, Mice, Mice, Transgenic, Mutation, Neoplastic Stem Cells, Stem Cell Niche, Transcriptome, Journal Article",

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 and Ian Tomlinson",

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 = "Elsevier",

number = "4",

}

Bardella, C, Al-Dalahmah, O, Krell, D, Brazauskas, P, Al-Qahtani, K, Tomkova, M, Adam, J, Serres, S, Lockstone, H, Freeman-Mills, L, Pfeffer, I, Sibson, N, Goldin, R, Schuster-Böeckler, B, Pollard, PJ, Soga, T, McCullagh, JS, Schofield, CJ, Mulholland, P, Ansorge, O, Kriaucionis, S, Ratcliffe, PJ, Szele, FG, Tomlinson, I & Tomlinson, I 2016, 'Expression of Idh1(R132H) in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis', Cancer Cell, vol. 30, no. 4, pp. 578-594. https://doi.org/10.1016/j.ccell.2016.08.017

TY - JOUR

T1 - Expression of Idh1(R132H) in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis

AU - Bardella, Chiara

AU - Al-Dalahmah, Osama

AU - Krell, Daniel

AU - Brazauskas, Pijus

AU - Al-Qahtani, Khalid

AU - Tomkova, Marketa

AU - Adam, Julie

AU - Serres, Sébastien

AU - Lockstone, Helen

AU - Freeman-Mills, Luke

AU - Pfeffer, Inga

AU - Sibson, Nicola

AU - Goldin, Robert

AU - Schuster-Böeckler, Benjamin

AU - Pollard, Patrick J

AU - Soga, Tomoyoshi

AU - McCullagh, James S

AU - Schofield, Christopher J

AU - Mulholland, Paul

AU - Ansorge, Olaf

AU - Kriaucionis, Skirmantas

AU - Ratcliffe, Peter J

AU - Szele, Francis G

AU - Tomlinson, Ian

PY - 2016/10/10

Y1 - 2016/10/10

N2 - 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.

AB - 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.

KW - Animals

KW - Brain Neoplasms

KW - DNA Methylation

KW - Glioma

KW - Isocitrate Dehydrogenase

KW - Lateral Ventricles

KW - Mice

KW - Mice, Transgenic

KW - Mutation

KW - Neoplastic Stem Cells

KW - Stem Cell Niche

KW - Transcriptome

KW - Journal Article

UR - https://www.scopus.com/pages/publications/84991800768

U2 - 10.1016/j.ccell.2016.08.017

DO - 10.1016/j.ccell.2016.08.017

M3 - Article

C2 - 27693047

SN - 1535-6108

VL - 30

SP - 578

EP - 594

JO - Cancer Cell

JF - Cancer Cell

IS - 4

ER -

Expression of Idh1(R132H) in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis

Abstract

UN SDGs

Keywords

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