Format

Send to

Choose Destination
Cell Rep. 2014 Sep 25;8(6):1974-1988. doi: 10.1016/j.celrep.2014.08.024. Epub 2014 Sep 18.

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

Author information

1
School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK.
2
School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
3
Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
4
Warwick Systems Biology Centre, University of Warwick, Coventry CV4 7AL, UK.
5
Section of Experimental Haematology, Leeds Institute for Molecular Medicine, University of Leeds, Leeds LS2 9JT, UK.
6
Cancer Science Institute, National University of Singapore, Republic of Singapore, Singapore 117456, Singapore.
7
School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.
8
Northern Institute for Cancer Research, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK. Electronic address: olaf.heidenreich@ncl.ac.uk.
9
School of Cancer Sciences, College of Medicine and Dentistry, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: c.bonifer@bham.ac.uk.

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.

PMID:
25242324
PMCID:
PMC4487811
DOI:
10.1016/j.celrep.2014.08.024
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center