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

• Published in: Cell reports (Cambridge) Vol. 35; no. 3; p. 109010
• Main Authors: Potluri, Sandeep, Assi, Salam A., Chin, Paulynn S., Coleman, Dan J.L., Pickin, Anna, Moriya, Shogo, Seki, Naohiko, Heidenreich, Olaf, Cockerill, Peter N., Bonifer, Constanze
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-04-2021; Elsevier
• Subjects: acute myeloid leukemia; Base Sequence; Cell Line, Tumor; Cell Movement; Cell Proliferation; chromatin; Chromatin - chemistry; Chromatin - metabolism; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Core Binding Factor Alpha 2 Subunit - genetics; Core Binding Factor Alpha 2 Subunit - metabolism; early growth response factors; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - metabolism; FLT3-ITD AML; fms-Like Tyrosine Kinase 3 - genetics; fms-Like Tyrosine Kinase 3 - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; HEK293 Cells; Humans; Leukemia, Myeloid, Acute - classification; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; oncogenic signaling; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; RUNX1 Translocation Partner 1 Protein - genetics; RUNX1 Translocation Partner 1 Protein - metabolism; Signal Transduction; Sp1 Transcription Factor - genetics; Sp1 Transcription Factor - metabolism; t(8;21) AML; transcription; Translocation, Genetic; Wilms tumour 1; WT1 binding motif; WT1 isoforms; WT1 Proteins - antagonists & inhibitors; WT1 Proteins - genetics; WT1 Proteins - metabolism; gene regulatory networks; oncogenic signaling; acute myeloid leukemia; transcription; FLT3-ITD AML; WT1 binding motif; chromatin; t(8;21) AML; Wilms tumour 1; WT1 isoforms; early growth response factors
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109010

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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•WT1 is an important factor for AML maintenance in multiple subtypes•WT1 acts in an isoform- and AML-subtype-specific fashion•WT1 binding to chromatin is in balance with early growth response factors•Upregulation of expression is part of an interlinked oncogenic signaling network
Potluri et al. demonstrate that in acute myeloid leukemia (AML), WT1 alters growth in an isoform-specific manner. It is regulated by oncogenic signaling and other oncogenes, plays a wide-spread role in AML biology, and is part of essential gene regulatory networks that maintain multiple leukemic subtypes.