Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.

Academic Article

Abstract

  • IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell-cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. In addition, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell-of-origin for glioma; thus, altering the progression of tumorigenesis. In addition, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.Implications: Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell-of-origin for gliomas. Mol Cancer Res; 15(5); 507-20. ©2017 AACR.
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    Keywords

  • Animals, Brain Neoplasms, Cell Differentiation, Cell Proliferation, Cells, Cultured, DNA Methylation, Gene Knock-In Techniques, Humans, Isocitrate Dehydrogenase, Lateral Ventricles, Mice, Mice, Transgenic, Mutation, Neural Stem Cells, Oligodendrocyte Transcription Factor 2, Promoter Regions, Genetic, Tumor Microenvironment
  • Digital Object Identifier (doi)

    Author List

  • Pirozzi CJ; Carpenter AB; Waitkus MS; Wang CY; Zhu H; Hansen LJ; Chen LH; Greer PK; Feng J; Wang Y
  • Start Page

  • 507
  • End Page

  • 520
  • Volume

  • 15
  • Issue

  • 5