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Genetic, Epigenetic and Molecular Sensitivity Landscape of Pediatric Rhabdomyosarcoma

Friday, September 18, 2015 — Poster Session IV

12:00 p.m. – 1:30 p.m.
FAES Terrace
NCI
GEN-18

* FARE Award Winner

Authors

  • BE Gryder
  • HC Chou
  • ME Yohe
  • YK Song
  • R Patidar
  • S Li
  • S Sindiri
  • A Cleveland
  • H Liao
  • X Wen
  • L Mathews-Griner
  • X Zhang
  • R Guha
  • P Shinn
  • M Ferrer
  • C Thomas
  • J Shern
  • J Khan

Abstract

Master transcription factors establish enhancers to regulate cell identity genes by recruiting epigenetic machinery, and are sequentially exchanged during changes in cell identity (ie, differentiation). Commonly, the fusion of transcription factors profoundly alters proper progression of cell identity, serving as the signature driving event in many malignancies. The most common soft tissue cancer of childhood, rhabdomyosarcoma (RMS), is characterized by an inability to exit the proliferative myoblast-like state, presumably by blocking myogenic transcription factors from advancing the active enhancer landscape. This is achieved by either chromosomal translocation resulting in the oncogenic fusion transcription factor PAX3/7-FOXO1 or mutations in the tyrosine kinase/RAS/PIK3C axis. Patients who harbor a PAX fusion typically relapse despite aggressive therapy, and have very poor survival. PAX-fusion tumors are marked by a strikingly low occurrence of mutations. PAX-fusions typically partner with FOXO1, but the same transcriptome can be achieved by PAX partnering with chromatin remodelers NCOA1 or INO80D. Master transcription factors (MYCN, MYOD1, MYOG) collaborate with PAX3-FOXO1 almost exclusively at distal enhancers. Active enhancer marks (H3K27ac, H3K4me1/2) found at PAX3-FOXO1 bound enhancers decrease over myogenic differentiation, including the super enhancer regulating MYOD1. Utilizing small molecule screening, we identified certain epigenetic modulators as unique protein dependencies, especially in PAX-fusion RMS. RNA-seq after treatment with epigenetic inhibitors reveals inactivation of PAX-fusion target genes. Collectively, our studies are pointing to epigenetic inhibition as a potential therapeutic option for children with PAX-fusion driven rhabdomyosarcoma.

Category: Genetics and Genomics