Analysis of target genes regulated by the PAX3-FKHR oncoprotein associated with alveolar rhabdomyosarcoma

The consistent association of hematopoietic and mesenchymal tumors with specific, balanced chromosomal translocations that generate chimeric oncogenes implicates the translocation products in the etiology of these cancers. This thesis focuses on the cellular consequences of the t(2;13)(q35;q14) chromosomal translocation associated with the pediatric tumor alveolar rhabdomyosarcoma. The translocation fuses portions of PAX3 and FKHR and generates the novel fusion oncogene PAX3-FKHR. PAX3 and FKHR are transcription factors critical to myogenic development and apoptotic/growth arrest signaling pathways, respectively. PAX3-FKHR also functions as a transcription factor and is postulated to contribute to the malignant phenotype of the alveolar rhabdomyosarcoma tumor cell by deregulating the tightly controlled process of target gene expression. Specifically, this thesis examines whether CXCR4, PAX3, PAX7, MET, IGF-IR, and BCL2L1 are downstream targets of the PAX3-FKHR oncoprotein. The identification of physiologically relevant PAX3-FKHR target genes will begin to elucidate the disrupted cellular pathways that contribute to ARMS tumor progression