Fusion Genes Resulting from Alternative Chromosomal Translocations are Overexpressed by Gene-Specific Mechanisms in Alveolar Rhabdomyosarcoma

Chromosomal translocations identified in hematopoietic and solid tumors result in deregulated expression of protooncogenes or creation of chimeric proteins with tumorigenic potential. In the pediatric solid tumor alveolar rhabdomyosarcoma, a consistent t(2;13) (q35;q14) or variant t(1;13)(p36;q14) t...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 1997-07, Vol.94 (15), p.8047-8051
Main Authors:	Davis, Richard J., Barr, Frederic G.
Format:	Article
Language:	eng
Subjects:	Alleles Biological Sciences Cell lines Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 13 Chromosomes, Human, Pair 2 Cloning, Molecular DNA-Binding Proteins - genetics Forkhead Box Protein O1 Forkhead Transcription Factors Fusion Genes Genetics Homeodomain Proteins Humans Muscle Proteins - genetics Nerve Tissue Proteins - genetics Paired Box Transcription Factors PAX3 Transcription Factor PAX7 Transcription Factor Plasmids Proteins Ratios Rhabdomyosarcoma Rhabdomyosarcoma, Alveolar - genetics RNA Transcription Factors - genetics Transcriptional Activation Translocation, Genetic Tumor cell line Tumor Cells, Cultured Tumors
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Summary:	Chromosomal translocations identified in hematopoietic and solid tumors result in deregulated expression of protooncogenes or creation of chimeric proteins with tumorigenic potential. In the pediatric solid tumor alveolar rhabdomyosarcoma, a consistent t(2;13) (q35;q14) or variant t(1;13)(p36;q14) translocation generates PAX3-FKHR or PAX7-FKHR fusion proteins, respectively. In this report, we demonstrate that in addition to functional alterations these translocations are associated with fusion product overexpression. Furthermore, PAX3-FKHR and PAX7-FKHR overexpression occurs by distinct mechanisms. Transcription of PAX3-FKHR is increased relative to wild-type PAX3 by a copy number-independent process. In contrast, PAX7-FKHR overexpression results from fusion gene amplification. Thus, gene-specific mechanisms were selected to overexpress PAX3-FKHR and PAX7-FKHR in alveolar rhabdomyosarcoma, presumably due to differences in regulation between the wild-type loci. We postulate that these overexpression mechanisms ensure a critical level of gene product for the oncogenic effects of these fusions.
ISSN:	0027-8424 1091-6490