PAX7-FKHR fusion gene inhibits myogenic differentiation via NF-kappaB upregulation

Elizabeth Charytonowicz, Igor Matushansky, Josep Domingo-Doménech, Mireia Castillo-Martín, Marc Ladanyi, Carlos Cordon-Cardo, Mel Ziman

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)197-206
Number of pages10
JournalClinical and Translational Oncology
Issue number3
StatePublished - Mar 2012


  • ARMS
  • NF-kappaB
  • PI3K/AKT

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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