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 rec...

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Bibliographic Details
Published in:G3 : genes - genomes - genetics 2015-02, Vol.5 (2), p.205-217
Main Authors: Galindo, Kathleen A, Endicott, Tiana R, Avirneni-Vadlamudi, Usha, Galindo, Rene L
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Drosophila - genetics
Drosophila Proteins - genetics
Embryo, Nonmammalian
Female
Forkhead Transcription Factors - genetics
Investigations
Male
Muscle Development - genetics
Myogenic Regulatory Factors - genetics
Nuclear Proteins - genetics
Paired Box Transcription Factors - genetics
Rhabdomyosarcoma - genetics
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Summary: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.
ISSN:2160-1836
2160-1836
DOI:10.1534/g3.114.015818