7852

CXCR4

CD184|D2S201E|FB22|HM89|HSY3RR|LAP3|LCR1|LESTR|NPY3R|NPYR|NPYRL|NPYY3R|WHIM;chemokine (C-X-C motif) receptor 4;CXCR4;chemokine (C-X-C motif) receptor 4

C-X-C chemokine receptor type 4|CD184 antigen|CXC-R4|CXCR-4|SDF-1 receptor|fusin|leukocyte-derived seven transmembrane domain receptor|leukocyte-derived seven-transmembrane-domain receptor|lipopolysaccharide-associated protein 3|neuropeptide Y receptor Y3

2q21

protein-coding

In the pediatric cancer alveolar rhabdomyosarcoma (ARMS), the 2;13 chromosomal translocation juxtaposes the PAX3 and FKHR genes to generate a chimeric transcription factor. To explore molecular pathways altered by this oncoprotein,we generated an inducible form by fusing PAX3-FKHR to a modified estrogen receptor ligand-binding domain and expressed this construct in the RD embryonal rhabdomyosarcoma cell line. This inducible system permits short-term evaluation of downstream expression targets of PAX3-FKHR and complements a panel of stable long-term RD subclones constitutively expressing PAX3-FKHR. Using these two setsof resources, we investigated several candidate PAX3-FKHR target genes. First, we demonstrated in both short-term and long-term systems that PAX3-FKHR upregulatesexpression of the gene encoding the chemokine receptor CXCR4. In addition, we found that expression of wild-type PAX3 is upregulated, whereas expression of wild-type PAX7 is downregulated by PAX3-FKHR. In the presence of cycloheximide, CXCR4 and PAX3 are still inducible, supporting the hypothesis that these genes are direct transcriptional targets of PAX3-FKHR. Finally, studies of ARMS tumorsrevealed CXCR4, PAX3, and PAX7 expression levels consistent with our cell culture results. These findings of genes regulated by PAX3-FKHR will direct future biological and clinical investigation to important pathways contributing to ARMStumorigenesis and progression.