Gene regulatory network analysis predicts cooperating transcription factor regulons required for FLT3-ITD+ AML growth
Daniel J.L. Coleman,
Peter Keane,
Rosario Luque-Martin,
Paulynn S. Chin,
Helen Blair,
Luke Ames,
Sophie G. Kellaway,
James Griffin,
Elizabeth Holmes,
Sandeep Potluri,
Salam A. Assi,
John Bushweller,
Olaf Heidenreich,
Peter N. Cockerill,
Constanze Bonifer
Affiliations
Daniel J.L. Coleman
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Peter Keane
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.
Rosario Luque-Martin
Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, UK
Paulynn S. Chin
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Helen Blair
Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle University, Herschel Building, Level 6, Brewery Lane, Newcastle upon Tyne NE1 7RU, UK
Luke Ames
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Sophie G. Kellaway
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
James Griffin
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Elizabeth Holmes
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Sandeep Potluri
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Salam A. Assi
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
John Bushweller
University of Virginia, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA
Olaf Heidenreich
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; Corresponding author
Peter N. Cockerill
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Corresponding author
Constanze Bonifer
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Corresponding author
Summary: 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.