Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth

Coleman, Daniel J.L.; Keane, Peter; Luque-Martin, Rosario; Chin, Paulynn S.; Blair, Helen; Ames, Luke; Kellaway, Sophie G.; Griffin, James; Holmes, Elizabeth; Potluri, Sandeep; Assi, Salam A.; Bushweller, John; Heidenreich, Olaf; Cockerill, Peter N.; Bonifer, Constanze

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease caused by different mutations. Previously, we showed that each mutational subtype develops its specific gene regulatory network (GRN) with transcription factors interacting within multiple gene modules, many of which are transcription factor genes themselves. Here, we hypothesize that highly connected nodes within such networks comprise crucial regulators of AML maintenance. We test this hypothesis using FLT3-ITD-mutated AML as a model and conduct an shRNA drop-out screen informed by this analysis. We show that AML-specific GRNs predict crucial regulatory modules required for AML growth. Furthermore, our work shows that all modules are highly connected and regulate each other. The careful multi-omic analysis of the role of one (RUNX1) module by shRNA and chemical inhibition shows that this transcription factor and its target genes stabilize the GRN of FLT3-ITD+ AML and that its removal leads to GRN collapse and cell death.

Citation

Coleman, D. J., Keane, P., Luque-Martin, R., Chin, P. S., Blair, H., Ames, L., Kellaway, S. G., Griffin, J., Holmes, E., Potluri, S., Assi, S. A., Bushweller, J., Heidenreich, O., Cockerill, P. N., & Bonifer, C. (2023). Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth. Cell Reports, 42(12), Article 113568. https://doi.org/10.1016/j.celrep.2023.113568

• Journal Article Type: Article
• Acceptance Date: Nov 27, 2023
• Online Publication Date: Dec 15, 2023
• Publication Date: Dec 26, 2023
• Deposit Date: Feb 14, 2024
• Publicly Available Date: Feb 16, 2024
• Journal: Cell Reports
• Electronic ISSN: 2211-1247
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 42
• Issue: 12
• Article Number: 113568
• DOI: https://doi.org/10.1016/j.celrep.2023.113568
• Keywords: FLT3-ITD acute myeloid leukemia; gene regulatory networks; shRNA drop-out screen; transcription factor regulatory modules; RUNX1 dependency
• Public URL: https://nottingham-repository.worktribe.com/output/31445811
• Publisher URL: https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01580-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124723015802%3Fshowall%3Dtrue
• PMID: 38104314
• Additional Information: This article is maintained by: Elsevier; Article Title: Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth; Journal Title: Cell Reports; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.celrep.2023.113568; Content Type: article; Copyright: © 2023 The Authors.