GNAQQ209L expression initiated in multipotent neural crest cells drives aggressive melanoma of the central nervous system

Abstract

Primary leptomeningeal melanocytic neoplasms represent a spectrum of rare tumors originating from melanocytes of the leptomeninges, which are the inner two membranes that protect the central nervous system. Like other non-epithelial melanocytic lesions, they bear frequent oncogenic mutations in the heterotrimeric G protein alpha subunits, GNAQ or GNA11. In this study, we used Plp1-creERT to force the expression of oncogenic GNAQ^Q209L in the multipotent neural crest cells of the ventro-medial developmental pathway, beginning prior to melanocyte cell differentiation. We found that this produces leptomeningeal melanocytic neoplasms, including cranial melanocytomas, spinal melanocytomas, and spinal melanomas, in addition to blue nevus-like lesions in the dermis. GNAQ^Q209L drove different phenotypes depending upon when during embryogenesis (E9.5, E10.5, or E11.5) it was induced by tamoxifen and which Cre driver (Plp1-creERT, Tyr-creERT² , or Mitf-cre) was used. Given these differences, we propose that melanocytes go through temporary phases where they become sensitive to the oncogenic effects of GNAQ^Q209L . R26-fs-GNAQ^Q209L ; Plp1-creERT mice will be useful for defining biomarkers for potentially aggressive leptomeningeal melanocytomas and for developing new therapeutics for advanced disease.

Keywords: GNAQ; Plp1; blue nevus; leptomeningeal melanocytoma; uveal melanoma.