Neurofibromin is a very large and complex protein that is able to synergize with multiple and diverse MAPK pathway components to drive melanoma. We have found that in mice, Nf1 haploinsufficiency induced at 5 weeks of age using Plp1-creERT accelerates the development of intra-dermal and uveal (ocular) melanoma in combination with expression of oncogenic GNAQ (Q209L), which is upstream of the classical MAPK pathway and also activates Yap. Heterozygous 17q11.2 loss that includes the NF1 locus is a rare, but recurrent phenomenon in human intra-dermal and uveal melanomas. Uploaded in this dataset is our RNAseq results of the mouse melanomas. They indicate that Nf1 loss up-regulates the cAMP signaling pathway and, surprisingly, down-regulates genes involved in muscle formation and function. In fact, 20% of the differentially expressed genes in the Nf1 mutant mouse melanomas were associated with patient survival in the TCGA uveal melanoma dataset, suggesting common pathways of importance. In addition, novel peripheral nerve sheath-like neoplasms were found, consistent with a recent GNAQ hotspot mutation discovery in MMNST (malignant melanotic nerve sheath tumor). The RNAseq experiments include these tumors as well.
Less...