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

Publication ,  Journal Article
Pirozzi, CJ; Carpenter, AB; Waitkus, MS; Wang, CY; Zhu, H; Hansen, LJ; Chen, LH; Greer, PK; Feng, J; Wang, Y; Bock, CB; Fan, P; Spasojevic, I ...
Published in: Mol Cancer Res
May 2017

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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Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

May 2017

Volume

15

Issue

5

Start / End Page

507 / 520

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Oligodendrocyte Transcription Factor 2
  • Neural Stem Cells
  • Mutation
  • Mice, Transgenic
  • Mice
  • Lateral Ventricles
  • Isocitrate Dehydrogenase
 

Citation

APA
Chicago
ICMJE
MLA
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Pirozzi, C. J., Carpenter, A. B., Waitkus, M. S., Wang, C. Y., Zhu, H., Hansen, L. J., … Yan, H. (2017). Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression. Mol Cancer Res, 15(5), 507–520. https://doi.org/10.1158/1541-7786.MCR-16-0485
Pirozzi, Christopher J., Austin B. Carpenter, Matthew S. Waitkus, Catherine Y. Wang, Huishan Zhu, Landon J. Hansen, Lee H. Chen, et al. “Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.Mol Cancer Res 15, no. 5 (May 2017): 507–20. https://doi.org/10.1158/1541-7786.MCR-16-0485.
Pirozzi CJ, Carpenter AB, Waitkus MS, Wang CY, Zhu H, Hansen LJ, et al. Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression. Mol Cancer Res. 2017 May;15(5):507–20.
Pirozzi, Christopher J., et al. “Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.Mol Cancer Res, vol. 15, no. 5, May 2017, pp. 507–20. Pubmed, doi:10.1158/1541-7786.MCR-16-0485.
Pirozzi CJ, Carpenter AB, Waitkus MS, Wang CY, Zhu H, Hansen LJ, Chen LH, Greer PK, Feng J, Wang Y, Bock CB, Fan P, Spasojevic I, McLendon RE, Bigner DD, He Y, Yan H. Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression. Mol Cancer Res. 2017 May;15(5):507–520.

Published In

Mol Cancer Res

DOI

EISSN

1557-3125

Publication Date

May 2017

Volume

15

Issue

5

Start / End Page

507 / 520

Location

United States

Related Subject Headings

  • Tumor Microenvironment
  • Promoter Regions, Genetic
  • Oncology & Carcinogenesis
  • Oligodendrocyte Transcription Factor 2
  • Neural Stem Cells
  • Mutation
  • Mice, Transgenic
  • Mice
  • Lateral Ventricles
  • Isocitrate Dehydrogenase