The role of PAX3/PAX7-FKHR in mesenchymal stem cell myogenic differentiation and rhabdomyosarcomagenesis

Rhabdomyosarcomas are soft tissue sarcomas (STS) that, while extremely rare in adults, are one of the most common neoplasms in children and adolescents. Rhabdomyosarcomas are presumed to be associated with the skeletal muscle lineage, although surprisingly, those tumors can be present in organs histologically lacking skeletal muscle, like prostate, urinary bladder or gallbladder. Pathologically, rhabdomyosarcomas are very heterogeneous tumors and can be divided into three major groups: alveolar rhabdomyosarcomas (ARMS), embryonal rhabdomyosarcomas (ERMS), which includes the botryoid subtype, and pleomorphic rhabdomyosarcomas. Besides clinicopathological differences, these tumors also differ at the molecular level. As in many other sarcoma types, ARMS are characterized by specific chromosomal translocations and almost 75% of cases show t(2;13) or t(1;13) translocations, involving PAX3-FKHR and PAX7-FKHR fusion genes respectively. These genetic events result in a molecular gain of function of the fusion protein, which is proposed to perturb the differentiation of muscle progenitor cells. Since PAX3/7-FKHR fusions result in rearrangements of PAX3/7 and FKHR genes, such that the PAX C-terminal domain is replaced by the potent FKHR transactivation domain, we sought to investigate the implications of this translocation on function and expression of wild type PAX3 and PAX7 Cterminal isoforms. This research identified functional differences between Pax3 and Pax7 Cterminal isoforms during myogenesis, and suggests that both Pax3 and Pax7 transcripts are required for commitment of cells to the myogenic lineage. More specifically, the Pax3c isoform may be required for terminal myogenic differentiation whereas the Pax3d isoform may be involved in undifferentiated cell maintenance and/or proliferation. Therefore, different levels of individual C-terminal isoforms of Pax3 and Pax7 in normal cells v may shift the balance between the undifferentiated and differentiated phenotype during muscle cell differentiation. In ARMS, this „balance‟ appears to be further disrupted and may lead to a block in terminal differentiation