Identification of new ETV6 modulators through a high-throughput functional screening

• Published in: iScience 2022-03, Vol.25 (3), p.103858-103858, Article 103858
• Main Authors: Neveu, Benjamin, Richer, Chantal, Cassart, Pauline, Caron, Maxime, Jimenez-Cortes, Camille, St-Onge, Pascal, Fuchs, Claire, Garnier, Nicolas, Gobeil, Stéphane, Sinnett, Daniel
• Format: Article
• Language: English
• Subjects: Cancer systems biology; Molecular biology; Omics
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2022.103858

ETV6 transcriptional activity is critical for proper blood cell development in the bone marrow. Despite the accumulating body of evidence linking ETV6 malfunction to hematological malignancies, its regulatory network remains unclear. To uncover genes that modulate ETV6 repressive transcriptional activity, we performed a specifically designed, unbiased genome-wide shRNA screen in pre-B acute lymphoblastic leukemia cells. Following an extensive validation process, we identified 13 shRNAs inducing overexpression of ETV6 transcriptional target genes. We showed that the silencing of AKIRIN1, COMMD9, DYRK4, JUNB, and SRP72 led to an abrogation of ETV6 repressive activity. We identified critical modulators of the ETV6 function which could participate in cellular transformation through the ETV6 transcriptional network. [Display omitted] •We develop a genome-wide shRNAs screen for ETV6 modulators•The screen uncovered 13 novel putative ETV6 modulator genes•The modulators demonstrated a broad impact on the ETV6 transcriptional network•T-ALL cells results suggest modulators are conserved in other cellular contexts Molecular biology; Cancer systems biology; Omics