The investigation of cell-cycle dependent expression of PAX3-FOXO1A in Rhabdomyosarcoma.

• Project/Area Number: 25893202
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pediatrics
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: KIKUCHI ken 京都府立医科大学, 医学(系)研究科(研究院), 助教 (40453104)
• Project Period (FY): 2013-08-30 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: PAX3-FOXO1 / 胞巣型横紋筋肉腫 / PAX3-FOXO1A / チェックポイントアダプテーション

Outline of Final Research Achievements

Rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by embryonal or alveolar histology (ARMS), which harbors a PAX3-FOXO1 fusion gene and has an extremely poor prognosis. Murine ARMS primary cultures were obtained from the Myf6Cre, PAX3-FOXO1, p53 conditional mouse model of ARMS. To elucidate the dynamical function of PAX3-FOXO1, time-lapse experiments, cell cycle analysis, QPCR, western blotting, immunohistochemistry, mRNA array and in vivo transplantation experiments were performed using murine ARMS primary cell culture with or without PAX3-FOXO1 knockdown treated by irradiation, or selected for ploidy using hoechst33342 sorted cell cycle-specific cells. The expression level of PAX3-FOXO1 was discovered to be dynamic and to vary during the cell cycle in murine and human ARMS cells. PAX3-FOXO1 is enriched in G2 and triggers at transcriptional program conducive to checkpoint adaptation in genome-wide expression analysis and QPCR.

Research Products

• [Journal Article] Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma. (2014)
  • Author(s): Kikuchi K, Hettmer S, Aslam MI, Michalek JE, Laub W, Wilky BA, Loeb DM, Rubin BP, Wagers AJ, Keller C
  • Journal Title: PLoS genetics. Volume: e1004107 Issue: 1 Pages: e1004107-e1004107
  • DOI: 10.1371/journal.pgen.1004107
  • Peer Reviewed / Open Access
• [Presentation] Effects of PAX3-FOXO1 in alveolar rhabdomyosarcoma. (2015)
  • Author(s): 菊地 顕、Simone Hettmer、Amy J. Wagers、Brian P. Rubin、Charles Keller、細井 創
  • Organizer: 第118回日本小児科学会学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2015-04-17 – 2015-04-19
• [Presentation] Cell-Cycle Dependent Expression of a Translocation-Mediated Fusion Oncogene Mediates Checkpoint Adaptation in Rhabdomyosarcoma (2014)
  • Author(s): Ken Kikuchi, Simone Hettmer, M. Imran Aslam, Joel E. Michalek, Wolfram Laub, Breelyn A. Wilky, David M. Loeb, Brian P. Rubin, Amy J. Wagers, Charles Keller, Hosoi Hajime
  • Organizer: 第56回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 2014-11-28 – 2014-11-30