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 journalArticlepeer-review

38 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

Bibliographical note

Funding Information:
We thank the members of the Koh, VanBrocklin, and Holmen labs as well as E. Holland, R. DePinho, and M. Bosenberg for providing mouse strains, reagents, and advice. We thank the Huntsman Cancer Institute (HCI) Vivarium staff for assistance with mouse husbandry. We thank Tim Parnell for bioinformatics expertise and Rowan Arave for assistance with the graphical abstract. We acknowledge the use of the Mass Spectrometry Core, the DNA Synthesis Core, the DNA Sequencing Core, the Small Animal Imaging Core, and the Drug Discovery Core at the University of Utah. We also acknowledge use of the HCI Shared Resources for High-Throughput Genomics and Bioinformatics analysis and the Biorepository Molecular Pathology (BMP) Research Histology Section supported by P30CA042014 awarded to HCI from the National Cancer Institute (NCI) . This work was supported by the National Institute of Neurological Disorders and Stroke ( R01NS075155 ) and NCI ( F30CA203096 ).

Funding Information:
We thank the members of the Koh, VanBrocklin, and Holmen labs as well as E. Holland, R. DePinho, and M. Bosenberg for providing mouse strains, reagents, and advice. We thank the Huntsman Cancer Institute (HCI) Vivarium staff for assistance with mouse husbandry. We thank Tim Parnell for bioinformatics expertise and Rowan Arave for assistance with the graphical abstract. We acknowledge the use of the Mass Spectrometry Core, the DNA Synthesis Core, the DNA Sequencing Core, the Small Animal Imaging Core, and the Drug Discovery Core at the University of Utah. We also acknowledge use of the HCI Shared Resources for High-Throughput Genomics and Bioinformatics analysis and the Biorepository Molecular Pathology (BMP) Research Histology Section supported by P30CA042014 awarded to HCI from the National Cancer Institute (NCI). This work was supported by the National Institute of Neurological Disorders and Stroke (R01NS075155) and NCI (F30CA203096).

Publisher Copyright:
© 2018 The Author(s)

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

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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