ARTICLE ABSTRACT
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.
