Abstract
The PAX3-FKHR fusion protein is present in a majority of alveolar rhabdomyosarcomas associated with increased aggressiveness and poor prognosis. To better understand the molecular pathogenesis of PAX3-FKHR, we carried out the first, unbiased genome-wide identification of PAX3-FKHR binding sites and associated target genes in alveolar rhabdomyosarcoma. The data shows that PAX3-FKHR binds to the same sites as PAX3 at both MYF5 and MYOD enhancers. The genome-wide analysis reveals that the PAX3-FKHR sites are (a) mostly distal to transcription start sites, (b) conserved, (c) enriched for PAX3 motifs, and (d) strongly associated with genes overexpressed in PAX3-FKHR-positive rhabdomyosarcoma cells and tumors. There is little evidence in our data set for PAX3-FKHR binding at the promoter sequences. The genome-wide analysis further illustrates a strong association between PAX3 and E-box motifs in these binding sites, suggestive of a common coregulation for many target genes. We also provide the first direct evidence that FGFR4 and IGF1R are the targets for PAX3-FKHR. The map of PAX3-FKHR binding sites provides a framework for understanding the pathogenic roles of PAX3-FKHR, as well as its molecular targets to allow a systematic evaluation of agents against this aggressive rhabdomyosarcoma.
(c)2010 AACR.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Anaplastic Lymphoma Kinase
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Binding Sites
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Cell Line, Tumor
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E-Box Elements
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Genome, Human
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Genome-Wide Association Study
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Humans
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MyoD Protein / genetics
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MyoD Protein / metabolism
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism
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Oncogene Proteins, Fusion / genetics*
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Oncogene Proteins, Fusion / metabolism
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 4 / genetics
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Receptor, IGF Type 1 / antagonists & inhibitors
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Receptor, IGF Type 1 / biosynthesis
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Receptor, IGF Type 1 / genetics
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Regulatory Elements, Transcriptional
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Rhabdomyosarcoma, Alveolar / genetics*
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Rhabdomyosarcoma, Alveolar / metabolism
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Sarcoma, Ewing / genetics
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Sarcoma, Ewing / metabolism
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Transcription Initiation Site
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Up-Regulation
Substances
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MYCN protein, human
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MyoD Protein
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MyoD1 myogenic differentiation protein
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N-Myc Proto-Oncogene Protein
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Nuclear Proteins
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Oncogene Proteins
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Oncogene Proteins, Fusion
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PAX3-FKHR fusion protein, human
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Anaplastic Lymphoma Kinase
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FGFR4 protein, human
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 4
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Receptor, IGF Type 1