Glioblastoma multiforme (GBM) is the most common type of primary malignant brain tumor and may arise from a cell with neural stem-like properties. Deregulation of the RB, PI3K and p53 pathways are molecular hallmarks of this disease. Recent work has demonstrated that p53-/-Pten-/- mice form gliomas in a c-Myc dependent manner. To explore the role of the INK4A/ARF locus and Pten deletions in gliomagenesis, we generated Pten-/-Ink4a/Arf-/- mNSCs and such cells were highly proliferative, self- renewing, relatively refractory to differentiation and induced both low and high grade glioma formation in vivo. In contrast to p53-/- Pten-/- mNSCs, however, Pten-/-Ink4a/Arf-/- mNSCs do not express appreciable levels of c-Myc in vitro although glioma stem cells (GSCs) derived from these same cells did. Sequencing of Pten-/-Ink4a/Arf-/-mNSCs- derived tumors revealed spontaneous mutations in Tp53 in vivo with subsequent downregulation of Fbxw7. Expression of p53 mutants in Pten-/-Ink4a/Arf-/- mNSCs, or knockdown of Fbxw7, resulted in re-expression of c-Myc with enhanced Pten-/-Ink4a/Arf- /- mNSCs tumorigenecity. We propose that p53 mutations contribute to gliomagenesis by both allowing the overexpression of c-Myc through downregulation of Fbxw7 and by protecting against c-Myc-induced apoptosis.

Citation Format: Hongsug Kim. Gliomagenesis arising from Pten- and Ink4a/Arf-deficient neural progenitor cells is mediated by the p53-Fbxw7/Cdc4 pathway, which controls c-Myc. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 353. doi:10.1158/1538-7445.AM2013-353