Keller and co-workers have knocked in a version of the Pax3:Fkhr fusion gene — believed to result in a gain-of-function mutation affecting muscle development — and at the same time generated the corresponding inactivation of one allele of Pax3 and one allele of Fkhr, carefully re-creating the genetic situation in the human disease. Importantly, the authors have targeted this mutation to be expressed only in terminally differentiating skeletal muscle. Their paper addressing Pax3:Fkhr expression in early development shows, through extensive use of different conditional mouse models, that the Pax3:Fkhr mutation in early precursor, embryonal and postnatal muscle stem cells seems unlikely to give rise to tumours, because of the presence of significant muscle defects during embryogenesis and the complete absence of tumour development in mice expressing Pax3:Fkhr in postnatal muscle stem cells.
The authors followed the development and growth of 228 Pax3:Fkhr mice over 29 months and only one animal developed a rhabdomyosarcoma during this time. So, to investigate what might increase the tumour incidence, the authors first examined if loss of the functional allele of Fkhr enhanced the tumorigenic process (as loss of Pax3 is known not to predispose to tumour formation), but no increase in tumour incidence was seen. Human alveolar rhabdomyosarcomas often have mutations in
TP53
or
CDKN2A
(which encodes INK4A and ARF), so Pax3:Fkhr mice were crossed with mice that had muscle-specific loss of one allele of either gene. Again, no increase in tumour incidence was seen, so the authors started to breed homozygotes for each gene. Their results show that rhabdomyosarcomas arise more frequently in these animals only in the absence of functional p53 pathways and mostly require Pax3:Fkhr homozygosity. Importantly, these mouse aveolar rhabdomyosarcomas were largely immunohistologically similar to those found in humans.
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