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RESEARCH PAPER
1 Division of Pediatric Hematology-Oncology and Department of Pediatrics, 2 Department of Human Genetics, 3 Division of Pediatric Pathology and Department of Pathology, and 4 Howard Hughes Medical Institute and Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA; 5 Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA
Alveolar rhabdomyosarcoma is an aggressive childhood muscle cancer for which outcomes are poor when the disease is advanced. Although well-developed mouse models exist for embryonal and pleomorphic rhabdomyosarcomas, neither a spontaneous nor a transgenic mouse model of alveolar rhabdomyosarcoma has yet been reported. We report the first mouse model of alveolar rhabdomyosarcoma using a conditional Pax3:Fkhr knock-in allele whose activation in late embryogenesis and postnatally is targeted to terminally differentiating Myf6-expressing skeletal muscle. In these mice, alveolar rhabdomyosarcomas occur but at low frequency, and Fkhr haploinsufficiency does not appear to accelerate tumorigenesis. However, Pax3:Fkhr homozygosity with accompanying Ink4a/ARF or Trp53 pathway disruption, by means of conditional Trp53 or Ink4a/ARF loss of function, substantially increases the frequencies of tumor formation. These results of successful tumor generation postnatally from a target pool of differentiating myofibers are in sharp contrast to the birth defects and lack of tumors for mice with prenatal and postnatal satellite cell triggering of Pax3:Fkhr. Furthermore, these murine alveolar rhabdomyosarcomas have an immunohistochemical profile similar to human alveolar rhabdomyosarcoma, suggesting that this conditional mouse model will be relevant to study of the disease and will be useful for preclinical therapeutic testing.
[Keywords: Alveolar rhabdomyosarcoma; Pax3:Fkhr; Pax3; Fkhr; FoxO1A; chromosome translocation; satellite cell]
Received July 26, 2004; revised version accepted September 3, 2004.
Article published online ahead of print. Article and publication date are at http://www.genesdev.org/cgi/doi/10.1101/gad.1244004.
6 Corresponding author.
E-MAIL mario.capecchi{at}genetics.utah.edu; FAX (801) 585-3425.
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