Abstract
The precise role played by the tumor suppressor gene NF1 in melanocyte biology and during the transformation into melanoma is not completely understood. In particular, understanding the interaction during melanocyte development between NF1 and key signaling pathways, which are known to be reactivated in advanced melanoma, is still under investigation. Here, we used RNAseq datasets from either situation to better understand the transcriptomic regulation mediated by an NF1 partial loss of function. We found that NF1 mutations had a differential impact on pluripotency and on melanoblast differentiation. In addition, major signaling pathways such as VEGF, senescence/secretome, endothelin, and cAMP/PKA are likely to be upregulated upon NF1 loss of function in both melanoblasts and metastatic melanoma. In sum, these data bring new light on the transcriptome regulation of the NF1-mutated melanoma subgroup and will help improve the possibilities for specific treatment.
Highlights
The implication of the NF1-encoded protein neurofibromin (NF1) in melanocyte biology has been investigated for more than 20 years
Three human induced pluripotent stem cell lines were generated from fibroblasts obtained from skin biopsies of two patients with Neurofibromatosis Type 1 carrying NF1 mutations (University of Ulm, Ulm, Germany), and three hiPSC lines were generated from three healthy donors (University Medical Center Mannheim, Mannheim, Germany) according to the ethical regulation
The transcriptome of NF1-mutated human induced pluripotent stem cells was analyzed by RNA sequencing and compared to wildtype control hiPSCs, in order to study the impact of NF1 mutations during reprogramming
Summary
The implication of the NF1-encoded protein neurofibromin (NF1) in melanocyte biology has been investigated for more than 20 years. Nf1+/− or Nf1−/− mice in which mutations were induced in the melanocyte lineage showed hyperpigmentation [3,4]. A partial rescue of the belly spot phenotype in MitfMi-wh/+ or cKitW/+ mice was observed when the latter were crossed with Nf1+/− mice [5,6]. These “café-au-lait” macules, which are benign melanocytic lesions, can be observed in almost all patients [7,8], and the cells located in the macules usually carry a second somatic mutation on the wildtype NF1 allele suggesting a selective advantage to the cell subpopulation [9]
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