Genomic alterations in spontaneous and carcinogen-induced murine melanoma cell lines

We have conducted an analysis of genetic alterations in spontaneous murine melanoma cell line B16F(0) and its two metastatic clones, B16F(1) and B16F(10) and the carcinogen-induced murine melanoma cell lines CM519, CM3205, and K1735. We found that unlike human melanomas, the murine melanoma cell lines did not have activating mutations in the Braf oncogene at exon 11 or 15. However, there were distinct patterns of alterations in the ras, Ink4a/Arf, and p53 genes in the two melanoma groups. In the spontaneous B16 melanoma cell lines, expression of p16(Ink4a) and p19(Arf) tumor suppressor proteins was lost as a consequence of a large deletion spanning Ink4a/Arf exons 1alpha, 1beta, and 2. In contrast, the carcinogen-induced melanoma cell lines expressed p16(Ink4a) but had inactivating mutations in either p19(Arf) (K1735) or p53 (CM519 and CM3205). Inactivation of p19(Arf) or p53 in carcinogen-induced melanomas was accompanied by constitutive activation of mitogen-activated protein kinases (MAPKs) and/or mutation-associated activation of N-ras. These results indicate that genetic alterations in p16(Ink4a)/p19(Arf), p53 and ras-MAPK pathways can cooperate in the development of murine melanoma.