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

• DOI: 10.1016/j.celrep.2021.109010
• Publication Date: 2021-04-21T04:00:40Z
• Authors: 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
• Keywords: 0301 basic medicine; Lung Neoplasms; Oncogene Proteins, Fusion; QH301-705.5; Chromosomes, Human, Pair 21; acute myeloid leukemia; 03 medical and health sciences; RUNX1 Translocation Partner 1 Protein; Cell Movement; Cell Line, Tumor; Humans; Protein Isoforms; Gene Regulatory Networks; Biology (General); RNA, Small Interfering; gene regulatory networks; t(8;21) AML; Cell Proliferation; Early Growth Response Protein 1; Base Sequence; Gene Expression Profiling; Chromatin; Gene Expression Regulation, Neoplastic; Leukemia, Myeloid, Acute; HEK293 Cells; Core Binding Factor Alpha 2 Subunit; chromatin; Wilms tumour 1; FLT3-ITD AML; Chromosomes, Human, Pair 8

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.