TMOD-04. DETERMINING THE NEUROANATOMICAL AND CELLULAR ORIGIN OF BRAFV600E MUTANT CDKN2A DELETED GLIOMAS AND MECHANISMS OF TRANSFORMATION BY BRAFV600E EXPRESSION IN TRANSGENIC MICE

Expression of the constitutively active BRAFV600E-mutant kinase occurs in pediatric and predominantly young adult high-grade glioma patients (Cancer Res. 2010, 70:512; Acta Neuropathol. 2011, 121:397). BRAFV600E expression frequently coincides with CDKN2A deletion and marks a subgroup of predominantly hemispheric tumors with epigenetic similarities to pleomorphic xanthastrocytoma (PXA) and histologic features of grade IV astrocytoma (Cancer Cell 2018, 33:829). The origin of BRAFV600E mutant astrocytoma is under investigation. Here, we are using transgenic mice to assess neuroanatomical aspects and effects on differentiation of BRAFV600E expression. In previous studies, expression of BRAFV600E in astroglial cells and neural stem cells of the developing brain led to hyperplasia in transgenic mice. To circumvent the early postnatal lethality associated with BRAFV600E expression during development, my lab injected adenovirus expressing Cre recombinase into the corpus callosum of BRAFCA Ink4a/Arf floxed young adult mice. In these mice, Cre expression induces BRAFV600E expression and deletion of Ink4a/Arf, the mouse locus homologous to human CDKN2A. This approach showed that BRAFV600E expression and CDKN2A (Ink4a/Arf) deficient corpus callosum cells form high-grade astrocytoma-like tumors in young adult mice (Proc Natl Acad Sci. 2012, 109:8710). To further investigate the neuroanatomical aspects of tumor formation we directed cre expression to distinct neuroanatomical areas, including the cortex, of the young adult mouse brain. Histo-pathologic and survival analyses showed that each injected area was susceptible to tumor formation albeit with different latency. Induction of BRAFV600E expression in Ink4a/Arf-deleted neurospheres in vitro decreased the capacity for neuronal and glial differentiation and led to expansion of oligodendrocyte progenitor-like cells (OPC). Ongoing studies investigate directly the extent to which BRAFV600E expression in Ink4a/Arf-deleted OPC in transgenic mice cause tumor formation. Results from cell of origin studies are expected to inform which mouse model most faithfully recapitulates the human diseases.