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.
Guida et al. (Mon,) studied this question.