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The Melanocyte-specific Isoform of the Microphthalmia Transcription Factor Affects the Phenotype of Human Melanoma¹

Department of Radiotherapy and Radiobiology [E. S., W. S.], Department of Clinical Pharmacology, Section of Experimental Oncology and Molecular Pharmacology [V. W., T. L., B. J.], Department of Dermatology, Division of General Dermatology [T. L., E. H-R., H. P., B. J.], Department of Internal Medicine I, Division of Hematology and Hemostaseology [P. V.], Department of Clinical Pathology [F. W.], Ludwig Boltzmann Institute for Clinical and Experimental Oncology [H. P.], and Center of Excellence for Clinical and Experimental Oncology, [E. S., H. P.], University Hospital Vienna, 1090 Vienna, Austria; Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [M. W., K. N. W., D. F.]; and Department of Medical Oncology, Washington University, St. Louis, Missouri 63110 [K. N. W.]

The microphthalmia transcription factor MITF plays a pivotal role in the development and differentiation of melanocytes. The purpose of this work was to investigate the expression and function of the melanocyte-specific isoform MITF-M in human melanoma. We found that MITF-M is repressed in 8 of 14 established melanoma cell lines tested. Transfection of MITF-M into a melanoma cell line (518A2) lacking the M-isoform and into a permanent cell line established from normal melanocytes (NMel-II) resulted in slower tumor growth in a severe combined immunodeficient-mouse xenotransplantation model. The growth difference between vector control-transfected tumors derived from the NMel-II cell line (mean tumor weight ± SD, 3.2 g ± 1.13) and MITF-M (+) transfectants (mean tumor weight ± SD, 1.1 g ± 0.49) was significant (P = 0.018). The mean tumor weight of control-transfected 518A2 tumors was 0.99 g ± 0.22 and of MITF-M (+) transfectants, 0.69 g ± 0.32. The difference in growth between 518A2 controls and the MITF-M (+) transfectants was clear, however it did not reach statistical significance (P = 0.08). In addition to the growth-inhibitory effects, MITF-M expression led to a change in the histopathological appearance of tumors from epitheloid toward a spindle-cell type in vivo. These results indicate a role for the MITF-M isoform in the in vivo growth control and the phenotype of human melanoma. In conclusion, MITF-M may qualify as a marker capable of identifying subgroups of melanoma patients with different tumor biology and prognosis.

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