Transcriptomic analysis of cell-of-origin CNS neuroblastoma, FOXR2 activated [CUT&RUN]

The transcription factor FOXR2 is the universal driver of childhood central nervous system neuroblastoma, FOXR2 activated (NB-FOXR2). NB-FOXR2 tumors arise exclusively in the brain hemispheres, and despite morphological similarities to other pediatric brain tumors, they are a molecularly distinct entity based on DNA methylation profiling. The cell-of-origin is unknown. Here, we profiled a cohort of rare NB-FOXR2 tumors by bulk and single-cell transcriptomics. Through systematic comparative analyses, we delineate tumor transcriptional states and candidate cell-of-origin. More broadly, we demonstrate systematic molecular profiling of childhood cancers to orient oncogenic targeting for in vivo modeling, a critical resource for the study of rare tumors and development of therapeutics. Overall design: CUT&RUN chromatin immunocleavage sequencing with antibody against V5 tag was performed on cell lines originating from genetically-engineered In utero electroporation(IUE) mouse models with brain tumor. 2 replicates on cell lines with FOXR2 p53LoF IUE vector containing the V5 tag and 2 replicates from cell lines of a separate IUE mouse model lacking V5 tag (G34R) as control were used.