Expression of Idh1R132H 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

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

Cancer Cell. 2016 Oct 10;30(4):578-594. doi: 10.1016/j.ccell.2016.08.017. Epub 2016 Sep 29.

Authors

Chiara Bardella¹, Osama Al-Dalahmah², Daniel Krell¹, Pijus Brazauskas³, Khalid Al-Qahtani⁴, Marketa Tomkova³, Julie Adam⁵, Sébastien Serres⁶, Helen Lockstone⁷, Luke Freeman-Mills¹, Inga Pfeffer⁴, Nicola Sibson⁸, Robert Goldin⁹, Benjamin Schuster-Böeckler³, Patrick J Pollard¹⁰, Tomoyoshi Soga¹¹, James S McCullagh⁴, Christopher J Schofield⁴, Paul Mulholland¹², Olaf Ansorge¹³, Skirmantas Kriaucionis³, Peter J Ratcliffe¹⁴, Francis G Szele¹⁵, Ian Tomlinson¹⁶

Affiliations

¹ Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
² Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
³ Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
⁴ Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
⁵ 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.
⁶ 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.
⁷ Bioinformatics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁸ Department of Oncology, Cancer Research UK and MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7LE, UK.
⁹ Centre for Pathology, St Mary's Hospital, Imperial College, London W2 1NY, UK.
¹⁰ 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.
¹¹ Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
¹² Department of Oncology, University College London Hospital, London NW1 2BU, UK.
¹³ Nuffield Department of Clinical Neurosciences, Department of Neuropathology, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
¹⁴ 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.
¹⁵ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK. Electronic address: francis.szele@dpag.ox.ac.uk.
¹⁶ Molecular & Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK. Electronic address: iant@well.ox.ac.uk.

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: DNA (hydroxy)methylation; Wnt; glioma; hydroxyglutarate; hydroxylase; isocitrate dehydrogenase; oncometabolite; stem cell; subventricular zone; α-ketoglutarate.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Brain Neoplasms / enzymology*
Brain Neoplasms / genetics
Brain Neoplasms / pathology
DNA Methylation
Glioma / enzymology*
Glioma / genetics
Glioma / pathology
Isocitrate Dehydrogenase / biosynthesis*
Isocitrate Dehydrogenase / genetics
Lateral Ventricles / enzymology*
Lateral Ventricles / pathology
Mice
Mice, Transgenic
Mutation
Neoplastic Stem Cells / enzymology*
Neoplastic Stem Cells / pathology
Stem Cell Niche*
Transcriptome

Substances

Isocitrate Dehydrogenase

Abstract

Publication types

MeSH terms

Substances

Grants and funding