Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1

Research output: Contribution to journalArticlepeer-review

Authors

Colleges, School and Institutes

External organisations

  • Chiba University Graduate School of Medicine
  • AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals Trust, Newcastle, UK.

Abstract

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.

Bibliographic note

Funding Information: We are grateful to the Genomics Birmingham Facility and to the University of Birmingham Flow Cytometry platform for their expert services. Furthermore, we thank Prof. Nick Hastie and Dr. Ruthrothaselvi Bharathavikru at the University of Edinburgh for advice on WT1 ChIP. This work was funded by a Medical Research Council and Leukaemia UK Clinical Research Training Fellowship to S.P. and by grants from Blood Cancer UK (specialist program grant 15001) and from the Medical Research Council (MR/S021469/1) to C.B. and P.N.C. S.P. designed the study, performed experiments, and wrote the paper. S.A.A. performed bioinformatics analyses. P.S.C. D.J.L.C. and A.P. performed experiments. S.M. and N.S. provided reagents. O.H. and P.N.C. supervised experiments. C.B. conceived, designed, and supervised the study and wrote the paper. The authors declare no competing financial interests. Publisher Copyright: © 2021 The Author(s)

Details

Original languageEnglish
Article number109010
Number of pages26
JournalCell Reports
Volume35
Issue number3
Publication statusPublished - 20 Apr 2021

Keywords

  • FLT3-ITD AML, WT1 binding motif, WT1 isoforms, Wilms tumour 1, acute myeloid leukemia, chromatin, early growth response factors, gene regulatory networks, oncogenic signaling, t(8;21) AML, transcription