Loss ofprdm1aaccelerates melanoma onset and progression

Melanoma is an aggressive, deadly skin cancer derived from melanocytes, a neural crest cell derivative. Melanoma cells mirror the developmental program of neural crest cells in that they exhibit the same gene expression patterns and utilize similar cellular mechanisms, including increased cell proliferation, EMT and migration. Here we studied the role of neural crest regulator PRDM1 in melanoma onset and progression. In development, Prdm1a functions to promote neural crest progenitor fate, and in melanoma, we found thatPRDM1has reduced copy number and is recurrently deleted in both zebrafish and humans. When examining expression of neural crest and melanocyte development genes, we show thatsox10progenitor expression is high inprdm1a-/-mutants, while more differentiated melanocyte markers are reduced, suggesting that normally Prdm1a is required for differentiation. Data mining of human melanoma datasets indicate that highPRDM1expression in human melanoma is correlated with better patient survival and decreasedPRDM1expression is common in metastatic tumors. When one copy ofprdm1ais lost in the zebrafish melanoma model (Tg[mitfa:BRAFV600E];p53-/-;prdm1a+ /-), melanoma onset occurs more quickly, and the tumors that form have a larger area with increased expression ofsox10.These data demonstrate a novel role for PRDM1 as a tumor suppressor in melanoma.