Data from Gliomagenesis Arising from Pten- and Ink4a/Arf-Deficient Neural Progenitor Cells Is Mediated by the p53-Fbxw7/Cdc4 Pathway, Which Controls c-Myc

Glioblastoma multiforme is the most common type of primary malignant brain tumor and may arise from a cell with neural stem-like properties. Deregulation of the retinoblastoma, phosphoinositide-3 kinase (PI3K), and p53 pathways are molecular hallmarks of this disease. Recent work has shown 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^−/− mouse neural stem cells (mNSC) 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 derived from thesecells did. Sequencing of Pten^−/−Ink4a/Arf^−/− mNSC–derived tumors revealed spontaneous mutations in Tp53 in vivo with subsequent downregulation of Fbxw7. Expression of p53 mutants in Pten^−/−Ink4a/Arf^−/− mNSC or knockdown of Fbxw7 resulted in reexpression of c-Myc with enhanced Pten^−/−Ink4a/Arf^−/− mNSC 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. Cancer Res; 72(22); 6065–75. ©2012 AACR.