NF1 encodes the multifunctional tumour suppressor protein, neurofibromin, which is best known for its causative role in Neurofibromatosis type 1 and in regulating MAPK signaling. Neurofibromin, in a context-specific manner, is involved in various tumorigenic processes, including those in melanocytes. This study investigated whether NF1 loss can collaborate with oncogenic GNAQ to promote melanoma in the dermis or eyes, where the G alpha q pathway is almost always activated. We found that heterozygous 17q11.2 loss that includes the NF1 locus is a recurrent phenomenon in human intra-dermal and uveal melanomas described in the literature. We studied the effects of Nf1 haploinsufficiency in mice expressing oncogenic GNAQ-Q209L in melanocytes and Schwann cells of peripheral nerves using the Plp1-creERT transgene, with tamoxifen at 5-weeks of age. Nf1 haploinsufficiency accelerated melanoma formation and/or growth. RNAseq analysis found significant pathways related to cAMP signaling and myogenesis. In addition, 20% of the differentially expressed genes were homologous to genes whose expression correlates with prognosis in human uveal melanoma. Unexpectedly, we found that GNAQ-Q209L alone was sufficient to drive cutaneous nerve sheath tumors, with one GNAQ-Q209L expressing Nf1 haploinsufficient mouse also developing a plexiform variant. These tumors strongly resembled neurofibromas. We searched the cBioPortal for Cancer Genomics database and found plexiform neurofibromas with the GNAQ T96S hotspot mutation. The Plp1-creERT; GNAQ-Q209L model with tamoxifen at 5 weeks may be useful as a pre-clinical model for neurofibroma. Our studies emphasize the importance of GNAQ and NF1 in regulating neural crest derived cells existing in a dermal-like environment.
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