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

Benjamin Neveu; Chantal Richer; Pauline Cassart; Maxime Caron; Camille Jimenez-Cortes; Pascal St-Onge; Claire Fuchs; Nicolas Garnier; Stéphane Gobeil; Daniel Sinnett

doi:10.1016/j.isci.2022.103858

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

iScience. 2022 Feb 2;25(3):103858. doi: 10.1016/j.isci.2022.103858. eCollection 2022 Mar 18.

Authors

Benjamin Neveu^{1

2}, Chantal Richer¹, Pauline Cassart¹, Maxime Caron^{1

3}, Camille Jimenez-Cortes^{1

4}, Pascal St-Onge¹, Claire Fuchs^{1

2}, Nicolas Garnier¹, Stéphane Gobeil^{5

6}, Daniel Sinnett^{1

7}

Affiliations

¹ Sainte-Justine University Health Center Research Center, Montreal, QC H3T 1C5, Canada.
² Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montreal, QC H3C 3J7, Canada.
³ Department of Human Genetics, McGill University, Montréal, QC H3A 0C7, Canada.
⁴ Molecular Biology Program, Faculty of Medicine, University of Montreal, Montreal, QC H3C 3J7, Canada.
⁵ CHU de Québec-Université Laval Research Center, Quebec City, QC G1V 4G2, Canada.
⁶ Department of Molecular Medicine, Faculty of Medicine, Université Laval, Quebec City, QC G1V 0A6, Canada.
⁷ Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, QC H3C 3J7, Canada.

Abstract

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.

Keywords: Cancer systems biology; Molecular biology; Omics.