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 GNAQQ209L 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. GNAQQ209L 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 GNAQQ209L . R26-fs-GNAQQ209L ; Plp1-creERT mice will be useful for defining biomarkers for potentially aggressive leptomeningeal melanocytomas and for developing new therapeutics for advanced disease.

中文翻译：

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在多能神经c细胞中启动的GNAQQ209L表达驱动中枢神经系统的侵袭性黑色素瘤。

原发性软脑膜黑素细胞瘤代表了一系列罕见的肿瘤，这些肿瘤起源于软脑膜的黑素细胞，它们是保护中枢神经系统的内部两层膜。像其他非上皮黑素细胞病变一样，它们在异三聚体G蛋白α亚基，GNAQ或GNA11中经常发生致癌突变。在这项研究中，我们使用Plp1-creERT迫使致癌性GNAQQ209L在黑素细胞分化之前开始在腹膜内侧发育途径的多能神经rest细胞中表达。我们发现，除了真皮中的蓝色痣样病变外，这还产生了软脑膜黑素细胞瘤，包括颅脑黑素细胞瘤，脊髓黑素细胞瘤和脊髓黑素瘤。GNAQQ209L根据胚胎发生的时间驱动不同的表型（E9.5，E10.5，或E11.5）由他莫昔芬诱导，并使用了Cre驱动程序（Plp1-creERT，Tyr-creERT2或Mitf-cre）。考虑到这些差异，我们建议黑素细胞经历临时阶段，在这些阶段中，它们对GNAQQ209L的致癌作用变得敏感。R26-fs-GNAQQ209L; Plp1-creERT小鼠可用于定义潜在侵袭性软脑膜黑素细胞瘤的生物标志物，以及开发针对晚期疾病的新疗法。