HG-13 * SOX9 AS A DOWN-STREAM TARGET IN RAS/MEK-DRIVEN PEDIATRIC GLIOMA

H. Sabelstrom, R. Jandial, K. Shchors, S. Masic, A. Ho, S. Vandenberg, T. P. Nicolaides, K. Nguyen, S. Yakovenko, M. D. Prados, C. D. James, M. S. Berger (+4 others)
2015 Neuro-Oncology  
Pediatric high-grade gliomas (pHGGs) represent approximately 8-12% of pediatric central nervous system (CNS) tumors and are associated with a dismal prognosis in patients. Genetic alterations in RAS/MEK/PI3K pathways and aberrant overexpression of receptor tyrosine kinases are a hallmark in glioma. We have recently shown that blockade of RAS/MEK, but not RAS/ PI3K signaling, in oligodendrocyte progenitor cell (OPC)-derived murine HGGs block self-renewal and induces robust oligodendrocyte
more » ... godendrocyte differentiation. To study if aberrant RAS/MEK signaling also prevents normal differentiation in astrocyte precursors, we employed a well-established astrocyte-derived HGG (GFAP-Ha V12 -Ras-LacZ, G-RAS) model. At birth, transgene expression (LacZ) was first identified in discrete regions, including the subventricular zone (SVZ). Expression of the transgene in SVZ neural stem cells (NSCs), but not OLIG2+ cells, resulted in an early postnatal astrocytoma formation and a progressive loss of neurogenesis. Treatment of SVZ tumorspheres from G-RAS mice and human GBMs, demonstrated that blockade of RAS/MEK, but not RAS/PI3K signaling, induced glial and neuronal differentiation. Treatment of premalignant G-RAS mice with the MEK inhibitor PD325901 completely restored neurogenesis. MEK inhibition in tumorsphere cultures effectively reduced expression of SOX9, a known barrier to neurogenesis. We confirmed that RNA interference of SOX9 induced neuronal differentiation in glioma cells. As one of the target genes of the neuronal determinant miR-124a, we demonstrate that reintroduction of miR-124a in HGG cells block SOX9 expression and induce neuronal differentiation. Our results suggest that a RAS/MEK/miR-124-SOX9 axis in the astrocyte lineage drives pediatric glioma formation.
doi:10.1093/neuonc/nov061.50 fatcat:csk2gbsyerhxngsdkfviyr5eym