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

Research output: Contribution to journalArticle

44 Citations (Scopus)

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 Idh1R132H 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. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

Original languageEnglish
Pages (from-to)578-594
Number of pages17
JournalCancer Cell
Volume30
Issue number4
DOIs
Publication statusPublished - 2016 Oct 10

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Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

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 Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis. Cancer Cell, 30(4), 578-594. https://doi.org/10.1016/j.ccell.2016.08.017