title: PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation.
abstract: OBJECTIVE
  Alveolar rhabdomyosarcomas (ARMS) are characterised by a PAX3/7-FKHR translocation, which is presumed to promote a differentiation arrest in the myogenic lineage, in which setting secondary genetic events occur, resulting in sarcomagenesis. The aim of this study was to identify the mechanism by which PAX3/7-FKHR expression results in a myogenic differentiation block, as discrete from the secondary genetic events that complete the sarcomagenic process.
  
  
  METHODS
  We performed a novel differential gene expression analysis comparing normal mesenchymal stem cells with previously generated non-tumorigenic mesenchymal stem cells expressing the PAX7-FKHR fusion gene, as well as with a known tumorigenic, PAX7-FKHR-expressing ARMS cell line, CW9019.
  
  
  RESULTS
  This novel analysis uncovered the upregulation of the NF-kappaB pathway as a function of PAX3/7-FKHR expression, but distinct from the secondary sarcomagenic process; thus implicating NF-kappaB as a mediator of the PAX3/7-FKHR differentiation block. We further show that NF-kappaB activity is upregulated in PAX7-FKHR cells when compared to parental MSCs due to upregulation of the PI3K/AKT pathway. In addition we show that NF-kappaB inhibits myogenesis via activation of cyclinD1/ cdk4 complexes, which sequester MyoD1, a key myogenic transcription factor.
  
  
  CONCLUSIONS
  Our results highlight the importance of the NF-kappaB pathway in myogenesis and sarcomagenesis and suggest that this pathway may be one of the potential therapeutic targets in the treatment of ARMS.
authors.affiliation: School of Exercise Biomedical and Health Science, Edith Cowan University, Joondalup, Western Australia 6027, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Charytonowicz
authors.forename: Igor
authors.initials: I
authors.lastname: Matushansky
authors.forename: Josep Domingo
authors.initials: JD
authors.lastname: Doménech
authors.forename: Mireia
authors.initials: M
authors.lastname: Castillo-Martín
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Mel
authors.initials: M
authors.lastname: Ziman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000502:physiology; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D024510:Muscle Development / Q000235:genetics* / Q000502:physiology; D032446:Myoblasts / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation
chemical_list: D016328:NF-kappa B; D015514:Oncogene Proteins, Fusion; C561715:PAX7-FKHR fusion protein, human