title: A rapid one-generation genetic screen in a Drosophila model to capture rhabdomyosarcoma effectors and therapeutic targets.
abstract: Rhabdomyosarcoma (RMS) is an aggressive childhood malignancy of neoplastic muscle-lineage 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-FOXO1-mediated 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.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Galindo
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072.
authors.forename: Tiana R
authors.initials: TR
authors.lastname: Endicott
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072.
authors.forename: Usha
authors.initials: U
authors.lastname: Avirneni-Vadlamudi
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072 Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072 Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072 rene.galindo@utsouthwestern.edu.
authors.forename: Rene L
authors.initials: RL
authors.lastname: Galindo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics*; D004625:Embryo, Nonmammalian; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D008297:Male; D024510:Muscle Development / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D051761:Paired Box Transcription Factors / Q000235:genetics*; D012208:Rhabdomyosarcoma / Q000235:genetics*
chemical_list: D029721:Drosophila Proteins; C477334:FOXO protein, Drosophila; D051858:Forkhead Transcription Factors; C499409:Mef2 protein, Drosophila; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D051761:Paired Box Transcription Factors; C085316:mam protein, Drosophila
keywords: PAX3-FOXO1; PAX7-FOXO1; myogenesis; rhabdomyosarcoma; sarcoma