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Cell Rep. 2018 May 1;23(5):1553-1564. doi: 10.1016/j.celrep.2018.03.133.

Mutant IDH1 Promotes Glioma Formation In Vivo.

Author information

1
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.
2
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.
3
Hormel Institute, University of Minnesota, 801 16(th) Avenue NE, Austin, MN 55912, USA.
4
Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, UT 84112, USA.
5
ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, UT 84108, USA.
6
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.
7
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.
8
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
9
Department of Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
10
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.
11
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. Electronic address: sheri.holmen@hci.utah.edu.

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.

KEYWORDS:

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

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