Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1
Sandeep Potluri,
Salam A. Assi,
Paulynn S. Chin,
Dan J.L. Coleman,
Anna Pickin,
Shogo Moriya,
Naohiko Seki,
Olaf Heidenreich,
Peter N. Cockerill,
Constanze Bonifer
Affiliations
Sandeep Potluri
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK; Corresponding author
Salam A. Assi
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK
Paulynn S. Chin
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK
Dan J.L. Coleman
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK
Anna Pickin
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK
Shogo Moriya
Department of Biochemistry and Genetics, Chiba University Graduate School of Medicine, Chiba, Japan
Naohiko Seki
Department of Functional Genomics, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan
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
Peter N. Cockerill
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK
Constanze Bonifer
Institute of Cancer and Genomic Sciences, College of Medicine and Dentistry, University of Birmingham, Edgbaston, Birmingham B152TT, UK; Corresponding author
Summary: Acute myeloid leukemia (AML) is caused by recurrent mutations in members of the gene regulatory and signaling machinery that control hematopoietic progenitor cell growth and differentiation. Here, we show that the transcription factor WT1 forms a major node in the rewired mutation-specific gene regulatory networks of multiple AML subtypes. WT1 is frequently either mutated or upregulated in AML, and its expression is predictive for relapse. The WT1 protein exists as multiple isoforms. For two main AML subtypes, we demonstrate that these isoforms exhibit differential patterns of binding and support contrasting biological activities, including enhanced proliferation. We also show that WT1 responds to oncogenic signaling and is part of a signaling-responsive transcription factor hub that controls AML growth. WT1 therefore plays a central and widespread role in AML biology.
