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Rhabdomyosarcoma fusion oncoprotein initially pioneers a neural signature in vivo

Jack Kucinski1, Alexi Tallan1, Cenny Taslim2

  • 1Molecular, Cellular, and Developmental Biology Program, The Ohio State University, Columbus, OH 43210, USA; Center for Childhood Cancer Research, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, OH 43215, USA.

Cell Reports
|July 4, 2025
PubMed

Insights

Fusion-positive rhabdomyosarcoma is driven by PAX3::FOXO1, which pioneers inaccessible chromatin. This binding activates neural programs, suggesting a key role in pediatric cancer initiation.

Area of Science:

  • Molecular biology
  • Developmental biology
  • Pediatric oncology

Background:

  • Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric cancer.
  • The PAX3::FOXO1 fusion oncogene drives FP-RMS by altering gene transcription.
  • Understanding PAX3::FOXO1's in vivo chromatin interactions is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the in vivo chromatin regulatory mechanisms of PAX3::FOXO1.
  • To characterize how PAX3::FOXO1 modulates chromatin during early developmental stages.
  • To identify potential therapeutic targets by understanding PAX3::FOXO1's genome binding and downstream effects.

Main Methods:

  • Development of a PAX3::FOXO1 zebrafish injection model.
  • Establishment of a semi-automated ChIP-seq normalization strategy.
  • Analysis of chromatin accessibility and histone modification (H3K27ac) changes upon PAX3::FOXO1 binding.

Main Results:

  • PAX3::FOXO1 exhibits pioneering activity, interacting with inaccessible chromatin via partial/homeobox motif recognition.
  • PAX3::FOXO1 binding alters chromatin accessibility and redistributes H3K27ac.
  • Activation of neural transcriptional programs by PAX3::FOXO1, including signatures relevant to clinical rhabdomyosarcoma.

Conclusions:

  • Partial/homeobox motif recognition is a key mechanism for PAX3::FOXO1 pioneer function.
  • PAX3::FOXO1-mediated activation of neural signatures may represent a critical event in rhabdomyosarcoma tumor initiation.
  • Findings provide insights into FP-RMS pathogenesis and potential therapeutic strategies.
Keywords:
CP: Cancerchromatin biologyfunctional epigenomicsfusion oncogenespediatric sarcomapioneer factorsrhabdomyosarcomazebrafish cancer models

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