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

doi:10.1016/j.celrep.2021.109010

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

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Article number	109010
Number of pages	26
Journal	Cell Reports
Volume	35
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109010
Publication status	Published - 20 Apr 2021

Bibliographical 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)

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

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

Access to Document

10.1016/j.celrep.2021.109010Licence: Creative Commons: Attribution (CC BY)

PotluriS2021IsoformFinal published version, 6.18 MBLicence: Creative Commons: Attribution (CC BY)

Finding therapeutic targets in FLT3-ITD AML using a systems biology approach
Cockerill, P. & Bonifer, C.
Medical Research Council
1/09/19 → 31/12/23
Project: Research Councils
Mechanistic insights into aberrant transcriptional programming in acute myeloid leukaemia
Bonifer, C. & Cockerill, P.
BLOODWISE
1/07/15 → 31/12/21
Project: Research

Cite this

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title = "Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1",

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.",

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author = "Sandeep Potluri and Assi, {Salam A} and Chin, {Paulynn S} and Coleman, {Dan J L} and Anna Pickin and Shogo Moriya and Naohiko Seki and Olaf Heidenreich and Cockerill, {Peter N} and Constanze Bonifer",

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: {\textcopyright} 2021 The Author(s)",

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AU - Assi, Salam A

AU - Chin, Paulynn S

AU - Coleman, Dan J L

AU - Pickin, Anna

AU - Moriya, Shogo

AU - Seki, Naohiko

AU - Heidenreich, Olaf

AU - Cockerill, Peter N

AU - Bonifer, Constanze

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N2 - 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.

AB - 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.

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KW - transcription

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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Projects

Finding therapeutic targets in FLT3-ITD AML using a systems biology approach

Mechanistic insights into aberrant transcriptional programming in acute myeloid leukaemia

Cite this