CS-34 EVIDENCE FOR OLIGODENDROCYTE ORIGINS OF PEDIATRIC GLIOMA

Malignant astrocytoma is a leading cause of cancer-related mortality in children. We have reported that activating mutations of serine/threonine protein kinase BRAF are present in 10 similar to 20% of pediatric glioma grade II-IV and are often accompanied by concomitant homozygous deletion of CDKN2A. In a de novo mouse model bearing similar genetic mutations (hGFAP-cre; BrafV600E(+/-); Ink-Arf-/-), we observed prolonged, increased and preferential proliferation of oligodendrocyte precursor (OLPs) versus astrocytes in the pre-cancerous state. These proliferative OLPs express several known cancer stem cell markers including Olig2, Sox2, Mash-1 and SSEA-1, suggesting further parallels with progenitors for pediatric glioma formation. We have previously shown that phosphorylation of Olig2 (P-Olig2) is associated with oncogenicity in adult glioma orthoptopic graphs. BrafV600E-activated OLPs express high levels of P-Olig2. A kinase inhibitor screen identified that GSK-3 beta and CK-II phosphorylate Olig2 in BrafV600E-driven neurospheres. Inhibition of CK-II resulted in decreased in P-Olig2 levels and OLP proliferation rate in vivo. Further pre-clinical studies are underway to validate the possible drugability of CK-II inhibitor and dual kinase inhibitor treatment with BrafV600E inhibitor. Our work suggests that OLPs may serve as cells-of-origin for pediatric glioma and that a inhibitor therapy targeted against P-Olig2 in Braf-driven pediatric glioma might have therapeutic benefit.