Reel, Sarah Martin

Abstract Background Oligodendrogliomas were previously defined by histology, but since 2016, the WHO has integrated molecular signatures to create the entity of IDH-mutant 1p/19q-codeleted oligodendroglioma. These tumors harbor recurrent genetic alterations—including IDH mutations, CIC and FUBP1 loss-of-function mutations, and PI3K-activating mutations—that collectively define a genetic profile distinct from IDH-mutant astrocytoma and IDH wild-type glioblastoma. The paucity of faithful model systems has impeded progress in advancing mechanistic insights and therapeutic development for oligodendroglioma. Results To test whether recurrent mutations found in oligodendroglioma patients would drive tumor formation in mice, we utilized in utero electroporation to introduce combinations of gain- and loss-of-function mutations into the developing cortex. Initial tests that included expression of IDH-and PIK3CA-mutants with Cic and Fubp1 loss (termed Oligo) were non-tumorigenic but biased cells towards glial lineages. Introducing Cdkn2a-loss, which is normally suppressed by IDH-associated epigenetic changes in human tumors, to the Oligo combination (termed Oligo-Cdkn2a) resulted in fully penetrant tumor formation. Histopathological review showed the Oligo Cdkn2a-loss mouse model resembled grade II/III oligodendroglioma with rounded nuclei and open chromatin. If Trp53-loss is used (termed Oligo-Trp53) in place of Cdkn2a-loss, tumor histology shifts to a more astrocytic phenotype with angulated nuclei with denser chromatin, demonstrating a direct impact of Trp53-loss on histological features. Bulk RNA-sequencing verifies metabolic alterations driven by the presence of IDH-mutations in Oligo-Cdkn2a mouse models compared to an IDH wild-type GBM model. Single-cell transcriptional profiling shows that Oligo-Cdkn2a tumors contain an increased population of tumor cells that resemble more differentiated oligodendrocytes. Examination of the tumor immune microenvironment within Oligo-Cdkn2a and IDHWT GBM mouse models is being performed to determine changes in immune cell infiltration and transcriptional programs. Conclusion We have created, to our knowledge, the first murine model of IDH-mutant 1p/19q-codeleted oligodendroglioma that incorporates Cic loss. This immune-competent mouse model of IDH-mutant 1p/19q-codeleted oligodendroglioma offers a powerful new tool for interrogating tumor biology and evaluating preclinical therapeutic strategies.

Abstract Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. Here we describe the generation of an IDH-mutant 1p/19q-codeleted oligodendroglioma mouse model using in utero electroporation. We identified IDH1 R132H , PIK3CA E545K , Cic KO , Fubp1 KO and Cdkn2a KO as the optimal combination (termed Oligo Cdkn2a ) to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant, 1p/19q-codeleted oligodendroglioma. Replacing Cdkn2a with Trp53 loss in this mouse model shifted tumor histology towards high grade astrocytoma. Oligo Cdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model. Oligo Cdkn2a tumors represent the first mouse model system to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas, offering a platform to further dissect tumor biology and test new therapeutic strategies.