Expression of Idh1R132Hin the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis.
Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132Hin 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. Idh1R132Hmutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.
Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Chiara
C
Bardella
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
Osama
O
Al-Dalahmah
Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Daniel
D
Krell
Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
Pijus
P
Brazauskas
Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Khalid
K
Al-Qahtani
Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
Marketa
M
Tomkova
Hypoxia Biology Laboratory, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK; Radcliffe Department of Medicine, OCDEM, Churchill Hospital, Oxford OX3 7LJ, UK.
Julie
J
Adam
Department of Oncology, Cancer Research UK and MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7LE, UK; School of Life Sciences, The Medical School, University of Nottingham, Nottingham NG7 2UH, UK.
Sébastien
S
Serres
Bioinformatics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Helen
H
Lockstone
Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Luke
L
Freeman-Mills
Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Inga
I
Pfeffer
Department of Oncology, Cancer Research UK and MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7LE, UK.
Nicola
N
Sibson
Centre for Pathology, St Mary's Hospital, Imperial College, London W2 1NY, UK.
Robert
R
Goldin
Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
Benjamin
B
Schuster-Böeckler
Hypoxia Biology Laboratory, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, 405 30 Gothenburg, Sweden.
Patrick J
PJ
Pollard
Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
Tomoyoshi
T
Soga
Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
James S
JS
McCullagh
Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Christopher J
CJ
Schofield
Department of Oncology, University College London Hospital, London NW1 2BU, UK.
Paul
P
Mulholland
Nuffield Department of Clinical Neurosciences, Department of Neuropathology, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
Olaf
O
Ansorge
Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
Skirmantas
S
Kriaucionis
Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK; Hypoxia Biology Laboratory, Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.
Peter J
PJ
Ratcliffe
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK. Electronic address: francis.szele@dpag.ox.ac.uk.
Francis G
FG
Szele
Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. Electronic address: iant@well.ox.ac.uk.
Ian
I
Tomlinson
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019175:DNA Methylation; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007521:Isocitrate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D020547:Lateral Ventricles / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000201:enzymology* / Q000473:pathology; D055153:Stem Cell Niche; D059467:Transcriptome
D007521:Isocitrate Dehydrogenase
DNA (hydroxy)methylation; Wnt; glioma; hydroxyglutarate; hydroxylase; isocitrate dehydrogenase; oncometabolite; stem cell; subventricular zone; α-ketoglutarate
J Inherit Metab Dis. 2015 Mar;38(2):273-7
25338511
Front Oncol. 2013 Jul 11;3:182
23875172
Cancer Cell. 2011 Jan 18;19(1):17-30
21251613
Science. 2009 Apr 10;324(5924):261-5
19359588
Nat Genet. 1999 Sep;23(1):99-103
10471508
Cancer Cell. 2012 Oct 16;22(4):425-37
23079654
J Clin Pathol. 2011 Oct;64(10):835-44
21752797
Brain Pathol. 2009 Jan;19(1):132-43
19076778
Hum Mol Genet. 2012 Feb 15;21(4):799-810
22068588
Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2829-34
25730874
J Neuropathol Exp Neurol. 2004 May;63(5):499-509
15198128
Nature. 2012 Aug 30;488(7413):656-9
22763442
Cells Tissues Organs. 2008;188(1-2):212-24
18223308
Neuron. 2011 May 26;70(4):674-86
21609824
Genes Dev. 2014 Mar 1;28(5):479-90
24589777
Science. 2008 Sep 26;321(5897):1807-12
18772396
Nat Commun. 2013;4:2166
23863747
Genes Dev. 2012 Sep 15;26(18):2038-49
22925884
EMBO Rep. 2011 May;12(5):463-9
21460794
Nat Neurosci. 2010 May;13(5):541-50
20418875
Cell. 2015 Nov 5;163(4):1011-25
26544944
Nature. 2009 Dec 10;462(7274):739-44
19935646
AJNR Am J Neuroradiol. 2012 May;33(5):940-3
22241392
J Natl Cancer Inst. 2010 Jul 7;102(13):932-41
20513808
N Engl J Med. 2009 Sep 10;361(11):1058-66
19657110
BMC Dev Biol. 2001;1:4
11299042
Cancer Cell. 2010 Dec 14;18(6):553-67
21130701
J Neurosci. 1997 Jul 1;17(13):5046-61
9185542
Nat Genet. 2011 Nov 06;43(12):1256-61
22057234
Nat Rev Mol Cell Biol. 2013 Jun;14(6):341-56
23698584
J Neurooncol. 2014 Nov;120(2):283-91
25085214
Oncogene. 2004 Sep 20;23(43):7267-73
15378086
Nat Commun. 2014 Mar 05;5:3423
24594748
Clin Cancer Res. 2006 Sep 15;12 (18):5288-97
17000661
J Clin Oncol. 2012 Apr 20;30(12):1350-7
22430270
Science. 1994 May 20;264(5162):1145-8
8178174
Oncologist. 2012;17(1):72-9
22180306
Genes Dev. 2011 Aug 1;25(15):1595-600
21828270
Genes Dev. 2010 Apr 1;24(7):683-95
20360385
N Engl J Med. 2009 Feb 19;360(8):765-73
19228619
J Neurosci. 2007 Nov 14;27(46):12623-9
18003841
Nature. 2012 Feb 15;483(7390):474-8
22343901
Genome Res. 2012 Dec;22(12):2339-55
22899282
J Neurooncol. 2009 Jan;91(2):233-6
18931888
J Cell Sci. 2011 Jul 15;124(Pt 14):2438-47
21693585
Genes Dev. 2013 Apr 15;27(8):836-52
23630074
Nat Genet. 2011 Nov 06;43(12):1262-5
22057236
Nat Rev Genet. 2001 Feb;2(2):120-9
11253051
Neurology. 2004 May 25;62(10):1882-4
15159502
Cancer Cell. 2010 Jan 19;17(1):98-110
20129251