Lister, J.A., Capper, A., Zeng, Z., Mathers, M.E., Richardson, J., Paranthaman, K., Jackson, I.J., and Patton, E.E. (2014) A Conditional Zebrafish MITF Mutation Reveals MITF Levels Are Critical for Melanoma Promotion vs. Regression In Vivo. The Journal of investigative dermatology. 134(1):133-40.
MITF is the ‘master melanocyte transcription factor’ with a complex role in melanoma. MITF protein levels vary between and within clinical specimens, and amplifications and gain- and loss-of function mutations have been identified in melanoma. How MITF functions in melanoma development and the effects of targeting MITF in vivo are unknown because MITF levels have not been directly tested in a genetic animal model. Here, we use a temperature-sensitive mitf zebrafish mutant to conditionally control endogenous MITF activity. We show that low-levels of endogenous MITF activity is oncogenic with BRAFV600E to promote melanoma that reflects the pathology of the human disease. Remarkably, abrogating MITF activity in BRAFV600Emitf melanoma leads to dramatic tumor regression marked by melanophage infiltration and increased apoptosis. These studies are significant because they show that targeting MITF activity is a potent anti-tumor mechanism, but also show that caution is required because low levels of wild type MITF activity is oncogenic.