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Fusion oncoproteins, which are well described in leukemias and lymphomas, are rare in carcinomas. An aggressive, undifferentiated carcinoma of young people, is defined by the presence of the BRD4-NUT fusion oncogene, resulting from a t(15;19)(q13;p13.1). Based on the knowledge that the study of the genes involved by recurrent translocations in acute leukemias and sarcomas have provided important insights into the pathways leading to oncogenesis, we sought to investigate the mechanism of epithelial cell transformation by BRD4-NUT. We find that NUT is a strong transcriptional activator when fused to the DNA-binding domain of Gal4, and that siRNA knockdown of BRD4-NUT in cell lines derived from BRD4-NUT carcinomas induces global changes in gene expression and striking changes in morphology, immunophenotype, and proliferation in vitro that are consistent with the induction of squamous differentiation. These changes were recapitulated in vivo using a nude mouse xenograft model. We conclude that BRD4-NUT is a unique oncoprotein that contributes to carcinogenesis by blocking terminal epithelial differentiation, a mechanism reminiscent of that ascribed to certain fusion proteins found in acute leukemias.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]