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 AnsorgeSkirmantas Kriaucionis, Peter J Ratcliffe, Francis G Szele, Ian Tomlinson, Ian Tomlinson

Cancer and Genomic Sciences

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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

Keywords

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

UN SDGs

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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. Advance online publication. https://doi.org/10.1016/j.ccell.2016.08.017

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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",

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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

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

Keywords

UN SDGs

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