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

Research output: Contribution to journalArticle

Authors

  • 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

Colleges, School and Institutes

External organisations

  • Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
  • Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK.
  • Nuffield Department of Clinical Medicine, Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
  • Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, United Kingdom
  • 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.
  • 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.
  • Bioinformatics, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • Department of Oncology, Cancer Research UK and MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7LE, UK.
  • Imperial College London
  • 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.
  • Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
  • Department of Oncology, University College London Hospital, London NW1 2BU, UK.
  • Nuffield Department of Clinical Neurosciences, Department of Neuropathology, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK.
  • 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.
  • Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK. Electronic address: francis.szele@dpag.ox.ac.uk.
  • 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.

Details

Original languageEnglish
Pages (from-to)578-594
Number of pages17
JournalCancer Cell
Volume30
Issue number4
Early online date29 Sep 2016
Publication statusPublished - 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