Mutant IDH1 Promotes Glioma Formation In Vivo

Beatrice Philip, Diana X. Yu, Mark R. Silvis, Clifford H. Shin, James P. Robinson, Gemma L. Robinson, Adam E. Welker, Stephanie N. Angel, Sheryl R. Tripp, Joshua A. Sonnen, Matthew W. VanBrocklin, Richard J. Gibbons, Ryan E. Looper, Howard Colman, Sheri L. Holmen

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Isocitrate dehydrogenase 1 (IDH1) is the most commonly mutated gene in grade II–III glioma and secondary glioblastoma (GBM). A causal role for IDH1R132H in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated. In this study, we assessed the role of IDH1R132H in glioma development in the context of clinically relevant cooperating genetic alterations in vitro and in vivo. Immortal astrocytes expressing IDH1R132H exhibited elevated (R)-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Although not sufficient on its own, IDH1R132H cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled proneural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1R132H promotes glioma development. This model enhances our understanding of the biology of IDH1R132H-driven gliomas and facilitates testing of therapeutic strategies designed to combat this deadly disease. Philip et al. show that mutant IDH1 cooperates with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote gliomagenesis in vivo in a mouse model of glioma. These tumors resemble proneural human mutant IDH1 glioblastoma and exhibit enhanced sensitivity to PARP inhibition in combination with chemotherapy.

Original languageEnglish (US)
Pages (from-to)1553-1564
Number of pages12
JournalCell Reports
Volume23
Issue number5
DOIs
StatePublished - May 1 2018

Keywords

  • Atrx
  • Cdkn2a
  • glioma
  • IDH1
  • mouse model
  • Pten
  • RCAS/TVA

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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  • Cite this

    Philip, B., Yu, D. X., Silvis, M. R., Shin, C. H., Robinson, J. P., Robinson, G. L., Welker, A. E., Angel, S. N., Tripp, S. R., Sonnen, J. A., VanBrocklin, M. W., Gibbons, R. J., Looper, R. E., Colman, H., & Holmen, S. L. (2018). Mutant IDH1 Promotes Glioma Formation In Vivo. Cell Reports, 23(5), 1553-1564. https://doi.org/10.1016/j.celrep.2018.03.133