The Senior Investigator moved to the National Cancer Institute during FY2011 and has been setting up the laboratory during the remaining time. Therefore no research studies were performed on this project during FY2011. However, in previous studies at the University of Pennsylvania, the Senior Investigator made the following observations. We have utilized a human myogenic system to study the PAX3-FOXO1 fusion in a cellular environment more relevant to alveolar rhabodmyosarcoma (ARMS). Starting with a human myoblast line immortalized with BMI1 and TERT, transduction with PAX3-FOXO1 and MYCN resulted in transforming and tumorigenic activities. The far majority of transduced cells expressed low PAX3-FOXO1 levels and did not have a transformed or tumorigenic phenotype. In contrast, only a small number of transduced cells expressed high PAX3-FOXO1 levels, and were transformed and tumorigenic. These findings are consistent with the toxicity of high PAX3-FOXO1 expression and the occurrence of cell autonomous changes allowing rare cells to circumvent the toxic effects of high-level expression. To investigate the relationship between phenotype and fusion protein level in a more dynamic system, we developed a 4-hydroxytamoxifen inducible system in which PAX3-FOXO1 is joined to a modified estrogen receptor ligand-binding domain. Using myoblasts transduced with MYCN and this inducible construct, we found that PAX3-FOXO1 induction results in transforming and tumorigenic activities, but also causes increasing growth suppression. Therefore, the inducible system will be useful for our studies of the mechanism of PAX3-FOXO1-induced toxicity.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Investigator-Initiated Intramural Research Projects (ZIA)
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National Cancer Institute Division of Basic Sciences
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Gryder, Berkley E; Yohe, Marielle E; Chou, Hsien-Chao et al. (2017) PAX3-FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability. Cancer Discov 7:884-899
Rudzinski, Erin R; Anderson, James R; Chi, Yueh-Yun et al. (2017) Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 64:
Poniewierska-Baran, Agata; Schneider, Gabriela; Sun, Wenyue et al. (2016) Human rhabdomyosarcoma cells express functional pituitary and gonadal sex hormone receptors: Therapeutic implications. Int J Oncol 48:1815-24
Xie, Zhongqiu; Babiceanu, Mihaela; Kumar, Shailesh et al. (2016) Fusion transcriptome profiling provides insights into alveolar rhabdomyosarcoma. Proc Natl Acad Sci U S A 113:13126-13131
Barr, Frederic G (2016) Fusion genes in solid tumors: the possibilities and the pitfalls. Expert Rev Mol Diagn 16:921-3
Arnold, Michael A; Anderson, James R; Gastier-Foster, Julie M et al. (2016) Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63:634-9
Olanich, Mary E; Sun, Wenyue; Hewitt, Stephen M et al. (2015) CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma. Clin Cancer Res 21:4947-59
Poniewierska-Baran, Agata; Suszynska, Malwina; Sun, Wenyue et al. (2015) Human rhabdomyosarcoma cells express functional erythropoietin receptor: Potential therapeutic implications. Int J Oncol 47:1989-97
Chen, Li; Shern, Jack F; Wei, Jun S et al. (2015) Clonality and evolutionary history of rhabdomyosarcoma. PLoS Genet 11:e1005075
Kohsaka, Shinji; Shukla, Neerav; Ameur, Nabahet et al. (2014) A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet 46:595-600

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