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

Cell Rep. 2021 Apr 20;35(3):109010. doi: 10.1016/j.celrep.2021.109010.

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: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • 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 Protein 1 / genetics
  • Early Growth Response Protein 1 / 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
  • 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
  • Translocation, Genetic
  • WT1 Proteins / antagonists & inhibitors
  • WT1 Proteins / genetics*
  • WT1 Proteins / metabolism
  • fms-Like Tyrosine Kinase 3 / genetics
  • fms-Like Tyrosine Kinase 3 / metabolism

Substances

  • Chromatin
  • Core Binding Factor Alpha 2 Subunit
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Oncogene Proteins, Fusion
  • Protein Isoforms
  • RNA, Small Interfering
  • RUNX1 Translocation Partner 1 Protein
  • RUNX1 protein, human
  • RUNX1T1 protein, human
  • Sp1 Transcription Factor
  • SP1 protein, human
  • WT1 Proteins
  • WT1 protein, human
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3