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

Autor:	Coleman DJL; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Keane P; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; School of Biosciences, University of Birmingham, Birmingham B15 2TT, U.K., Luque-Martin R; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, UK., Chin PS; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Blair H; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, UK., Ames L; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Kellaway SG; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Griffin J; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Holmes E; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Potluri S; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Assi SA; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK., Bushweller J; University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA., Heidenreich O; Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, UK; Prinses Máxima Centrum for Pediatric Oncology, Postbus 113, 3720 AC Bilthoven, Heidelberglaan 25, 3584CS Utrecht, the Netherlands. Electronic address: o.t.heidenreich@prinsesmaximacentrum.nl., Cockerill PN; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: p.n.cockerill@bham.ac.uk., Bonifer C; Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: c.bonifer@bham.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2023 Dec 26; Vol. 42 (12), pp. 113568. Date of Electronic Publication: 2023 Dec 15.
DOI:	10.1016/j.celrep.2023.113568
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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