Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis

被引：119

作者：

Bardella, Chiara ^{[1
]}

Al-Dalahmah, Osama ^{[2
]}

Krell, Daniel ^{[1
]}

Brazauskas, Pijus ^{[3
]}

Al-Qahtani, Khalid ^{[4
]}

Tomkova, Marketa ^{[3
]}

Adam, Julie ^{[5
,6
]}

Serres, Sebastien ^{[7
,8
]}

Lockstone, Helen ^{[9
]}

Freeman-Mills, Luke ^{[1
]}

Pfeffer, Inga ^{[4
]}

Sibson, Nicola ^{[7
]}

Goldin, Robert ^{[10
]}

Schuster-Boeckler, Benjamin ^{[3
]}

Pollard, Patrick J. ^{[5
,11
]}

Soga, Tomoyoshi ^{[12
]}

McCullagh, James S. ^{[4
]}

Schofield, Christopher J. ^{[4
]}

Mulholland, Paul ^{[13
]}

Ansorge, Olaf ^{[14
]}

Kriaucionis, Skirmantas ^{[3
]}

Ratcliffe, Peter J. ^{[3
,5
]}

Szele, Francis G. ^{[2
]}

Tomlinson, Ian ^{[1
]}

机构：

[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Mol & Populat Genet Lab, Oxford OX3 7BN, England

[2] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England

[3] Univ Oxford, Ludwig Inst Canc Res, Nuffield Dept Clin Med, Oxford OX3 7DQ, England

[4] Univ Oxford, Chem Res Lab, Oxford OX1 3TA, England

[5] Univ Oxford, Henry Wellcome Bldg Mol Physiol, Hypoxia Biol Lab, Oxford OX3 7BN, England

[6] Churchill Hosp, OCDEM, Radcliffe Dept Med, Oxford OX3 7LJ, England

[7] Univ Oxford, Canc Res UK & MRC Oxford Inst Radiat Oncol, Dept Oncol, Oxford OX3 7LE, England

[8] Univ Nottingham, Sch Med, Sch Life Sci, Nottingham NG7 2UH, England

[9] Univ Oxford, Wellcome Trust Ctr Human Genet, Bioinformat, Oxford OX3 7BN, England

[10] Imperial Coll, St Marys Hosp, Ctr Pathol, London W2 1NY, England

[11] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, S-40530 Gothenburg, Sweden

[12] Keio Univ, Inst Adv Biosci, 246-2 Mizukami, Tsuruoka, Yamagata 9970052, Japan

[13] Univ Coll London Hosp, Dept Oncol, London NW1 2BU, England

[14] John Radcliffe Hosp, Dept Neuropathol, Nuffield Dept Clin Neurosci, Headley Way, Oxford OX3 9DU, England

来源：

CANCER CELL | 2016年 / 30卷 / 04期

基金：

英国惠康基金;

关键词：

INTEGRATED GENOMIC ANALYSIS; IDH2; MUTATIONS; ONCOMETABOLITE; 2-HYDROXYGLUTARATE; OLLIER DISEASE; MOUSE MODELS; MUTANT IDH; CANCER; DEMETHYLATION; MIGRATION; ACIDURIA;

D O I：

10.1016/j.ccell.2016.08.017

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 alpha-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded,, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gate 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.

引用

页码：578 / 594

页数：17

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