Alveolar rhabdomyosarcomas in conditional Pax3:Fkhr mice: cooperativity of Ink4a/ARF and Trp53 loss of function.
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.
Keller
Charles
C
Division of Pediatric Hematology-Oncology and Department of Pediatrics, University of Utah, Salt Lake City, Utah 84112, USA.
Arenkiel
Benjamin R
BR
Coffin
Cheryl M
CM
El-Bardeesy
Nabeel
N
DePinho
Ronald A
RA
Capecchi
Mario R
MR
D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D005818:Genetic Engineering / Q000379:methods; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018006:Myogenic Regulatory Factors; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; C063403:myogenic factor 6; C068686:Pax3 protein, mouse; D020727:ADP-Ribosylation Factors