Summary of patient samples included in this study, and profiling by RNAseq, scRNAseq, or scMultiome.

NB-FOXR2 tumors transcriptionally resemble interneurons and oligodendrocyte precursor cells.

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 IDH1R132H, PIK3CAE545K, Cic KO, Fubp1 KO and Cdkn2a KO as the optimal combination (termed OligoCdkn2a) 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. OligoCdkn2a 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. OligoCdkn2a 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.

Summary of reference datasets for the normal brain and adrenal gland used in this study.

Bulk RNAseq projections by ssGSEA.

Schematic illustration of ER and cell cycle pathway signaling, and pathway analysis from phase 0/1 letrozole clinical trial RNA-seq data

Quality control metrics and processing parameters for single-cell data for murine models.

Orthotopic engraftment of cell lines derived from Foxr2 p53LOF murine model.

Cell type specific gene signatures derived from reference datasets, used for enrichment scoring.

Quality control (QC) metrics and copy-number variation for scRNAseq datasets of NB-FOXR2 patient tumors.

Dose-response matrices for patient-derived GBM lines G75, G43, JHH-136 and G59 and HSA synergy model

ssGSEA enrichment of cell type specific gene signatures in bulk RNAseq tumors. For each sample, the highest scoring signature is shown.

Combination index plots for cell viability at IC50: G75, G43, JHH-136 & G59 to assess the nature of interaction of ribociclib and LTZ combination.

Reference dataset labels used for cell type annotation of mouse model single-cell datasets.

Quantification of expression and detection rate (Pct1) for transcription factors in the normal brain reference datasets.

IC50 values for LTZ, ribociclib and combination of ribociclib with non-cytotoxic concentrations of LTZ against patient-derived GBM lines and EC50 values for neurosphere growth inhibition.

Mouse models transcriptomically recapitulate human NB-FOXR2

Transcription factor (TF) patterning in normal reference datasets.

Microscopic analysis of the cytotoxic effects of ribociclib and LTZ on neurosphere growth of the G75, G43, JHH-136 and G59 cells.

Post-alignment quality control for bulk RNAseq data for pediatric brain tumors.