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Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells

Author:
  • Tove Ullmark
  • Linnea Järvstråt
  • Carl Sanden
  • Giorgia Montano
  • Helena Jernmark-Nilsson
  • Henrik Lilljebjörn
  • Andreas Lennartsson
  • Thoas Fioretos
  • Kristina Drott
  • Karina Vidovic
  • Björn Nilsson
  • Urban Gullberg
Publishing year: 2017
Language: English
Pages: 336-345
Publication/Series: Haematologica
Volume: 102
Document type: Journal article
Publisher: Ferrata Storti Foundation

Abstract english

The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is rather enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with involvement of WT1 in acute myeloid leukemia.

Keywords

  • Hematology
  • Medical Genetics

Other

Published
  • Transcriptional mechanisms for the Wilms’ tumor gene 1 (WT1) oncoprotein
  • Lymphoma - Clinical Research
  • ISSN: 1592-8721
Thoas Fioretos
E-mail: thoas [dot] fioretos [at] med [dot] lu [dot] se

Principal investigator

Translational Genomic and Functional Studies of Leucemia

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66

Professor

Division of Clinical Genetics

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66

Professor

Translational Genomic and Functional Studies of Leucemia

+46 46 222 45 95

+46 70 334 33 67

BMC C13

66