Identification of a STAT5 target gene, Dpf3, provides novel insights in chronic lymphocytic leukemia

PLoS One. 2013 Oct 14;8(10):e76155. doi: 10.1371/journal.pone.0076155. eCollection 2013.

Abstract

STAT5 controls essential cellular functions and is encoded by two genes, Stat5a and Stat5b. To provide insight to the mechanisms linking hematologic malignancy to STAT5 activation/regulation of target genes, we identified STAT5 target genes and focused on Dpf3 gene, which encodes for an epigenetic factor. Dpf3 expression was induced upon IL-3 stimulation in Ba/F3 cells, while strong binding of both STAT5a and STAT5b was detected in its promoter. Reduced expression of Dpf3 was detected in Ba/F3 cells with Stat5a and Stat5b knock-down, suggesting that this gene is positively regulated by STAT5, upon IL-3 stimulation. Furthermore, this gene was significantly up-regulated in CLL patients, where DPF3 gene/protein up-regulation and strong STAT5 binding to the DPF3 promoter, correlated with increased STAT5 activation, mainly in non-malignant myeloid cells (granulocytes). Our findings provide insights in the STAT5 dependent transcriptional regulation of Dpf3, and demonstrate for the first time increased STAT5 activation in granulocytes of CLL patients. Novel routes of investigation are opened to facilitate the understanding of the role of STAT5 activation in the communication between non-malignant myeloid and malignant B-cells, and the functions of STAT5 target genes networks in CLL biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • DNA-Binding Proteins / genetics*
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Gene Expression Regulation, Leukemic / drug effects
  • Gene Library
  • Genome, Human / genetics
  • HEK293 Cells
  • Humans
  • Interleukin-3 / pharmacology
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Mice
  • Promoter Regions, Genetic / genetics
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • STAT5 Transcription Factor / metabolism*
  • Transcription Factors / genetics*
  • Tumor Suppressor Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • DPF3 protein, human
  • Interleukin-3
  • RNA, Messenger
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • STAT5B protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins

Grant support

This work was supported by research funding from the EU (European Reintegration Grant) and BRFAA to EK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.