Abstract
Glioblastoma Multiforme (GBM) is a malignant primary brain tumor. Genomic analysis of GBMs revealed somatic mutations associated with particular subtypes, which correlate with age at the time of diagnosis. Young adult GBMs include a mutation in Isocitrate Dehydrogenase 1 gene (IDH1-R132H) and mutations in epigenetic regulators, ATRX and H3.3G34, which define an epigenetic and biological subgroup. IDH1-R132H results in gain of an alternative enzymatic function producing the metabolite 2-hydroxglutarate (2HG) and alterations in histone methylation patterns. Animal models are critical to study and understand disease progression and pathogenesis; therefore we developed an in vivo model of young adult GBM through expression of IDH1-R132H, H3.G34 and ATRX knockdown in neonatal mouse brain using the Sleeping Beauty Transposase system. In this model we are studying the effects of these genetic lesions in tumor development and DNA repair mechanisms. The tumors were induced by injection of NRAS and shP53 plasmids in the lateral ventricle of C57BL/6 neonatal mice with or without pKT/IDH1-R132H, Pkt/H3.G34 or PT2/shATRX. Plasmid delivery into stem cells lining the lateral ventricle and tumor progression was monitored by luciferase imaging. The tumors were also used to generate neurospheres for genetic analysis; moribund animals were perfused and analyzed using immunocytochemistry. IDH1-R132H expression increased the levels of H3K27me3 and enhanced median survival of the mice. The groups representing young adult GBM: NRAS/shP53/shATRX/IDH1-R132H and NRAS/shP53/shATRX/H3.G34 also exhibited increased survival compared with the control (NRAS/shP53) and the pediatric (NRAS/shP53/shATRX) groups. Mice developed brain tumors harboring key features of young adult GBMs. We aim to determine the impact of these genetic lesions in median survival, tumor progression and DNA repair mechanisms “in vivo”. Supported by NIH-NINDS grants, the Department of Neurosurgery and Leah's Happy Hearts Foundation to MGC and PRL, and very generous support from Phil F. Jenkins.
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