Sox2 protein stability is enhanced by BRafV600E and Pten deletion in adult neural stem/progenitor cells

BRAF mutations are oncogenic drivers present in about 7% of human cancers, with the V600E substitution being the most frequent. In the nervous system, BRAFV600E has been identified in both low- and high-grade gliomas (LGG and HGG) and in tumors of the peripheral nervous system. To investigate the mechanisms underlying BRafV600E-driven tumorigenesis, we generated a mouse model in which the BRafV600E mutation and Pten deletion can be induced through the Sox2-CreERT2 system. This inducible deleter is active in adult neural stem/progenitor cells (aNSPCs) and Schwann cell precursors (SCPs). In this model, BRafV600E-mutated/Pten-deleted telencephalic aNSPCs give rise to diffuse LGG with oligodendroglioma-like features resembling the human diffuse LGG, MAPK pathway–altered subtype. In contrast, mutated SCPs develop schwannomas, cutaneous neurofibromas, and malignant peripheral nerve sheath tumors (MPNSTs). Sox2 deletion in BRafV600E/Ptendel mice markedly reduces tumor formation, indicating that aNSPCs act as tumor cells of origin. In vitro analyses show increased proliferation of BRafV600E/Ptendel aNSPCs and preferential differentiation toward oligodendroglia-like tumor cells. BRaf-mutant aNSPCs display increased Sox2 protein, but not mRNA levels, suggesting post-transcriptional regulation. Sox2 phosphorylation at T118 is promoted by BRafV600E, potentially stabilizing the protein during aNSPC transformation, although the involvement of downstream kinases cannot be excluded.