Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Diana X. Yu
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Mark R. Silvis
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Clifford H. Shin
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
James P. Robinson
Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA
Gemma L. Robinson
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Adam E. Welker
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Stephanie N. Angel
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Sheryl R. Tripp
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108, USA
Joshua A. Sonnen
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108, USA; Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Matthew W. VanBrocklin
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Richard J. Gibbons
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
Ryan E. Looper
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA
Howard Colman
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Neurosurgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA
Sheri L. Holmen
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA; Corresponding author
Summary: 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. Keywords: IDH1, Cdkn2a, Atrx, Pten, glioma, mouse model, RCAS/TVA
