A rapid one-generation genetic screen in a drosophila model to capture rhabdomyosarcoma effectors and therapeutic targets

Kathleen A. Galindo, Tiana R. Endicott, Usha Avirneni-Vadlamudi, Rene L. Galindo

Research output: Contribution to journalArticle

1 Scopus citations


Rhabdomyosarcoma (RMS) is an aggressive childhood malignancy of neoplastic musclelineage precursors that fail to terminally differentiate into syncytial muscle. The most aggressive form of RMS, alveolar-RMS, is driven by misexpression of the PAX-FOXO1 oncoprotein, which is generated by recurrent chromosomal translocations that fuse either the PAX3 or PAX7 gene to FOXO1. The molecular underpinnings of PAX-FOXO12mediated RMS pathogenesis remain unclear, however, and clinical outcomes poor. Here, we report a new approach to dissect RMS, exploiting a highly efficient Drosophila PAX7-FOXO1 model uniquely configured to uncover PAX-FOXO1 RMS genetic effectors in only one generation. With this system, we have performed a comprehensive deletion screen against the Drosophila autosomes and demonstrate that mutation of Mef2, a myogenesis lynchpin in both flies and mammals, dominantly suppresses PAX7-FOXO1 pathogenicity and acts as a PAX7-FOXO1 gene target. Additionally, we reveal that mutation of mastermind, a gene encoding a MEF2 transcriptional coactivator, similarly suppresses PAX7-FOXO1, further pointing toward MEF2 transcriptional activity as a PAX-FOXO1 underpinning. These studies show the utility of the PAX-FOXO1 Drosophila system as a robust one-generation (F1) RMS gene discovery platform and demonstrate how Drosophila transgenic conditional expression models can be configured for the rapid dissection of human disease.

Original languageEnglish (US)
Pages (from-to)205-217
Number of pages13
JournalG3: Genes, Genomes, Genetics
Issue number2
StatePublished - Jan 1 2015



  • Myogenesis
  • PAX3-FOXO1
  • PAX7-FOXO1
  • Sarcoma
  • rhabdomyosarcoma

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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