Immature skin cells depend on the transcription factor MITF for survival, growth and commitment to the melanocyte lineage. Levi Garraway and colleagues now show that MITF is also required for the survival, development and progression of melanoma, and call MITF a lineage-survival oncogene.

The authors found that six of eight melanoma cell lines in the NCI60 panel of tumour cell lines had a region of gene amplification on chromosome 3p, and that MITF seemed to be the target of this amplification. Examination of human tumours showed that no benign moles had amplification of MITF, but 10% of primary melanomas and 21% of metastatic melanomas did. In addition, MITF amplification was associated with decreased 5-year survival of patients with metastatic melanoma.

MITF represses cell proliferation by activating inhibitors of the cell cycle, including the tumour suppressor INK4A. INK4A is probably inactivated early in melanoma progression and, indeed, the NCI60 cell-lines that contained amplified MITF also contained inactivated INK4A. These cell lines also had activating mutations in BRAF, a vital signalling factor in melanocytes. To examine the role of MITF further, Garraway and colleagues introduced MITF and/or activated BRAF into melanocytes in which cell-cycle-inhibitor pathways, including the INK4A pathway, had been inactivated, and that were dependent on the addition of certain factors to the cell-culture medium for survival. BRAF activation alone led to some factor-independent growth, but only co-expression of MITF and BRAF led to factor independence and transformation of the melanocytes. Introduction of dominant-negative MITF, or knockdown of MITF with short hairpin RNAs, led to growth inhibition of the NCI60 melanoma cell lines.

So, MITF has a crucial lineage-survival function in melanoma, but does it influence a patient's response to chemotherapy? The authors carried out a supervised analysis of the pharmacological data on the NCI60 cell lines and found that cell lines with MITF amplification were more resistant to chemotherapeutic agents than those without. When dominant-negative MITF was introduced into these cell lines, the chemosensitivity of the cells increased.

The authors conclude that MITF is an essential lineage-survival factor in melanoma cells and might be a useful marker for the selection of appropriate treatment or as a target for therapy.