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

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 aggressi...

Source: Molecular Cancer Research - May 1, 2017 Category: Cancer & Oncology Authors: Pirozzi, C. J., Carpenter, A. B., Waitkus, M. S., Wang, C. Y., Zhu, H., Hansen, L. J., Chen, L. H., Greer, P. K., Feng, J., Wang, Y., Bock, C. B., Fan, P., Spasojevic, I., McLendon, R. E., Bigner, D. D., He, Y., Yan, H. Tags: Cell Cycle and Senescence Source Type: research