EWSR1 and FUS fusion genes in tumorigenesis

Sammanfattning: The present thesis concerns the involvement of EWSR1 and FUS fusion genes, and the chimeric proteins they encode, in tumorigenesis. In Article I, the EWSR1 promoter, which regulates the expression of EWSR1 fusion genes, was characterized and regions that were crucial for promoter activity could be identified. The sequence was found to have bidirectional activity and is likely to regulate also RHBDD3, another cancer-associated gene. In Article II, the EWSR1-POU5F1 fusion was found in hidradenoma and mucoepidermoid carcinoma, the first report of EWSR1 fusion genes in epithelial tumor types. The EWSR1-POU5F1 chimera was a stronger transcriptional activator than wild-type (wt) POU5F1, analogous to other EWSR1 chimeras, and was able to activate transcription through a binding site which is normally recognized by POU5F1. In Article III, FUS-CREB3L2 was found to be a stronger transcriptional activator than wt CREB3L2 and to activate transcription through binding sites normally recognized by CREB3L2. Also, the results suggest that the chimera is regulated by intramembrane proteolysis like wt CREB3L2. In Article IV, low-grade fibromyxoid sarcoma (LGFMS), which is characterized by the FUS-CREB3L2 fusion, was found to have a specific gene expression profile, compared to histologically similar tumors types. Binding sites for FOXL1, the top upregulated gene in LGFMS, and other FOX factors were overrepresented in the promoters of LGFMS-upregulated genes, suggesting an important function of FOX factors in LGFMS.CD24 was upregulated in the tumors and FUS-CREB3L2 expressing cells, and FUS-CREB3L2 was able to activate transcription through a CD24 regulatory sequence.