Abstract LB-20: Transcriptionally inactive PAX3-FKHR fails to induce ARMS cells differentiation

Alveolar rhabdomyosarcoma (ARMS) is an aggressive muscle cancer of childhood and believed to arise from committed muscle progenitor cells that have arrested during the process of skeletal muscle differentiation. One of the most established genetic signatures in ARMS is the presence of chimeric aberrant transcription factor PAX3-FKHR generated by fusion of PAX3 and FKHR genes. The stronger transcriptional activity of this fusion PAX3-FKHR protein has previously been attributed to the deregulation of genes, which are known to be associated with tumorigenesis and suppression of skeletal muscle differentiation. Currently, we are investigating the relative contribution of PAX3-FKHR's transcriptional activity in abrogating ARMS cells differentiation using mouse ARMS cells as an in vitro model differentiation readout system. Here, we show that transactivation potential of PAX3-FKHR is declined in mouse ARMS cells that have been induced to differentiate by growing these cells in mitogens-deficient in vitro differentiation-permissible condition. Moreover, this diminished activity of PAX3-FKHR is not due to the alteration of its sub-cellular localization or changes in the level of either mRNA or protein in these ARMS cells. Results also show the lack of muscle-specific gene activation in these ARMS cells despite the reduced transcriptional activity of PAX3-FKHR under condition of differentiation. We also observed that decrease in transcriptional activity of PAX3-FKHR is coincided with the activation of PI3/AKT pathway. The results further show that blockade of PI3/AKT pathway sustains the transcriptional activity of PAX3-FKHR whereas forced activation of AKT inhibits this activity. Together, our results signify that transcriptionally inactive PAX3-FKHR by AKT is incompetent to induce mouse ARMS cells differentiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-20.