A quantitative proteomics approach identifies ETV6 and IKZF1 as new regulators of an ERG-driven transcriptional network

Ashwin Unnikrishnan, Yi F Guan, Yizhou Huang, Dominik Beck, Julie A I Thoms, Sofie Peirs, Kathy Knezevic, Shiyong Ma, Inge V de Walle, Ineke de Jong, Zara Ali, Ling Zhong, Mark J Raftery, Tom Taghon, Jonas Larsson, Karen L MacKenzie, Pieter Van Vlierberghe, Jason W H Wong, John E Pimanda

Research output: Contribution to journalArticlepeer-review

11 Citations (SciVal)

Abstract

Aberrant stem cell-like gene regulatory networks are a feature of leukaemogenesis. The ETS-related gene (ERG), an important regulator of normal haematopoiesis, is also highly expressed in T-ALL and acute myeloid leukaemia (AML). However, the transcriptional regulation of ERG in leukaemic cells remains poorly understood. In order to discover transcriptional regulators of ERG, we employed a quantitative mass spectrometry-based method to identify factors binding the 321 bp ERG +85 stem cell enhancer region in MOLT-4 T-ALL and KG-1 AML cells. Using this approach, we identified a number of known binders of the +85 enhancer in leukaemic cells along with previously unknown binders, including ETV6 and IKZF1. We confirmed that ETV6 and IKZF1 were also bound at the +85 enhancer in both leukaemic cells and in healthy human CD34+ haematopoietic stem and progenitor cells. Knockdown experiments confirmed that ETV6 and IKZF1 are transcriptional regulators not just of ERG, but also of a number of genes regulated by a densely interconnected network of seven transcription factors. At last, we show that ETV6 and IKZF1 expression levels are positively correlated with expression of a number of heptad genes in AML and high expression of all nine genes confers poorer overall prognosis.

Original languageEnglish
Pages (from-to)10644-10661
JournalNucleic Acids Research
Volume44
Issue number22
DOIs
Publication statusPublished - 2016 Dec 15

Bibliographical note

© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Subject classification (UKÄ)

  • Medical Genetics
  • Microbiology in the medical area

Keywords

  • Base Sequence
  • Binding Sites
  • Cell Line, Tumor
  • Consensus Sequence
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Leukemic
  • Gene Regulatory Networks
  • Humans
  • Ikaros Transcription Factor/physiology
  • Kaplan-Meier Estimate
  • Leukemia, Myeloid, Acute/genetics
  • Prognosis
  • Proportional Hazards Models
  • Protein Binding
  • Proteome
  • Proteomics
  • Proto-Oncogene Proteins c-ets/physiology
  • Repressor Proteins/physiology
  • Transcription, Genetic
  • Transcriptional Regulator ERG/physiology

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