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

Group Heidenreich

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

21 Citations (Scopus)

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
Pages (from-to)	109010
Journal	Cell reports
Volume	35
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109010
Publication status	Published - 20 Apr 2021

Keywords

Base Sequence
Cell Line, Tumor
Cell Movement
Cell Proliferation
Chromatin/chemistry
Chromosomes, Human, Pair 21
Chromosomes, Human, Pair 8
Core Binding Factor Alpha 2 Subunit/genetics
Early Growth Response Protein 1/genetics
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Gene Regulatory Networks
HEK293 Cells
Humans
Leukemia, Myeloid, Acute/classification
Lung Neoplasms/genetics
Oncogene Proteins, Fusion/genetics
Protein Isoforms/antagonists & inhibitors
RNA, Small Interfering/genetics
RUNX1 Translocation Partner 1 Protein/genetics
Signal Transduction
Sp1 Transcription Factor/genetics
Translocation, Genetic
WT1 Proteins/antagonists & inhibitors
fms-Like Tyrosine Kinase 3/genetics

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10.1016/j.celrep.2021.109010

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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.",

keywords = "Base Sequence, Cell Line, Tumor, Cell Movement, Cell Proliferation, Chromatin/chemistry, Chromosomes, Human, Pair 21, Chromosomes, Human, Pair 8, Core Binding Factor Alpha 2 Subunit/genetics, Early Growth Response Protein 1/genetics, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, HEK293 Cells, Humans, Leukemia, Myeloid, Acute/classification, Lung Neoplasms/genetics, Oncogene Proteins, Fusion/genetics, Protein Isoforms/antagonists \& inhibitors, RNA, Small Interfering/genetics, RUNX1 Translocation Partner 1 Protein/genetics, Signal Transduction, Sp1 Transcription Factor/genetics, Translocation, Genetic, WT1 Proteins/antagonists \& inhibitors, fms-Like Tyrosine Kinase 3/genetics",

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",

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doi = "10.1016/j.celrep.2021.109010",

language = "English",

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pages = "109010",

journal = "Cell reports",

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T1 - Isoform-specific and signaling-dependent propagation of acute myeloid leukemia by Wilms tumor 1

AU - Potluri, Sandeep

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

PY - 2021/4/20

Y1 - 2021/4/20

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.

KW - Base Sequence

KW - Cell Line, Tumor

KW - Cell Movement

KW - Cell Proliferation

KW - Chromatin/chemistry

KW - Chromosomes, Human, Pair 21

KW - Chromosomes, Human, Pair 8

KW - Core Binding Factor Alpha 2 Subunit/genetics

KW - Early Growth Response Protein 1/genetics

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Gene Regulatory Networks

KW - HEK293 Cells

KW - Humans

KW - Leukemia, Myeloid, Acute/classification

KW - Lung Neoplasms/genetics

KW - Oncogene Proteins, Fusion/genetics

KW - Protein Isoforms/antagonists & inhibitors

KW - RNA, Small Interfering/genetics

KW - RUNX1 Translocation Partner 1 Protein/genetics

KW - Signal Transduction

KW - Sp1 Transcription Factor/genetics

KW - Translocation, Genetic

KW - WT1 Proteins/antagonists & inhibitors

KW - fms-Like Tyrosine Kinase 3/genetics

UR - https://www.scopus.com/pages/publications/85104277014

U2 - 10.1016/j.celrep.2021.109010

DO - 10.1016/j.celrep.2021.109010

M3 - Article

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SP - 109010

JO - Cell reports

JF - Cell reports

IS - 3

M1 - 109010

ER -

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

Abstract

Keywords

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