Stem cell-like cells have recently been identified in melanoma cell lines, but 
their relevance for melanoma pathogenesis is controversial. To characterize the 
stem cell signature of melanoma, expression of stem cell markers BMI-1 and 
nestin was studied in 64 cutaneous melanomas, 165 melanoma metastases as well as 
53 melanoma cell lines. Stem cell renewal factor BMI-1 is a transcriptional 
repressor of the Ink4a/Arf locus encoding p16(ink4a) and p14(Arf). Increased 
nuclear BMI-1 expression was detectable in 41 of 64 (64%) primary melanomas, 117 
of 165 melanoma metastases (71%) and 15 of 53 (28%) melanoma cell lines. High 
nestin expression was observed in 14 of 56 primary melanomas (25%), 84 of 165 
melanoma metastases (50%) and 21 of 53 melanoma cell lines (40%). There was a 
significant correlation between BMI-1 and nestin expression in cell lines (p = 
0.001) and metastases (p = 0.02). These data indicate that cells in primary 
melanomas and their metastases may have stem cell properties. Cell lines 
obtained from melanoma metastases showed a significant higher BMI-1 expression 
compared to cell lines from primary melanoma (p = 0.001). Further, primary 
melanoma lacking lymphatic metastases at presentation (pN0, n = 40) was less 
frequently BMI-1 positive than melanomas presenting with lymphatic metastases 
(pN1; n = 24; 52% versus 83%; p = 0.01). Therefore, BMI-1 expression appears to 
induce a metastatic tendency. Because BMI-1 functions as a transcriptional 
repressor of the Ink4a/Arf locus, p16(ink4a) and p14(Arf) expression was also 
analyzed. A high BMI-1/low p16(ink4a) expression pattern was a significant 
predictor of metastasis by means of logistic regression analysis (p = 0.005). 
This suggests that BMI-1 mediated repression of p16(ink4a) may contribute to an 
increased aggressive behavior of stem cell-like melanoma cells.