TY - JOUR
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
N1 - Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
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 - http://www.scopus.com/inward/record.url?scp=85104277014&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2021.109010
DO - 10.1016/j.celrep.2021.109010
M3 - Article
C2 - 33882316
SN - 2211-1247
VL - 35
SP - 109010
JO - Cell reports
JF - Cell reports
IS - 3
M1 - 109010
ER -