Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal

Research output: Contribution to journalArticlepeer-review

Authors

External organisations

  • Newcastle University
  • The University of Warwick
  • University of Leeds
  • Cancer Science Institute, National University of Singapore

Abstract

Oncogenic transcription factors such as RUNX1/ETO, which is generated by the chromosomal translocation t(8;21), subvert normal blood cell development by impairing differentiation and driving malignant self-renewal. Here, we use digital footprinting and chromatin immunoprecipitation sequencing (ChIP-seq) to identify the core RUNX1/ETO-responsive transcriptional network of t(8;21) cells. We show that the transcriptional program underlying leukemic propagation is regulated by a dynamic equilibrium between RUNX1/ETO and RUNX1 complexes, which bind to identical DNA sites in a mutually exclusive fashion. Perturbation of this equilibrium in t(8;21) cells by RUNX1/ETO depletion leads to a global redistribution of transcription factor complexes within preexisting open chromatin, resulting in the formation of a transcriptional network that drives myeloid differentiation. Our work demonstrates on a genome-wide level that the extent of impaired myeloid differentiation in t(8;21) is controlled by the dynamic balance between RUNX1/ETO and RUNX1 activities through the repression of transcription factors that drive differentiation.

Details

Original languageEnglish
Pages (from-to)1974-1988
Number of pages15
JournalCell Reports
Volume8
Issue number6
Early online date18 Sep 2014
Publication statusPublished - 25 Sep 2014