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Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal

Lookup NU author(s): Dr Daniel Williamson, Professor Olaf Heidenreich

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


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 foot-printing 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.


Publication metadata

Author(s): Ptasinska A, Assi SA, Martinez-Soria N, Imperato MR, Piper J, Cauchy P, Pickin A, James SR, Hoogenkamp M, Williamson D, Wu MC, Tenen DG, Ott S, Westhead DR, Cockerill PN, Heidenreich O, Bonifer C

Publication type: Article

Publication status: Published

Journal: Cell Reports

Year: 2014

Volume: 8

Issue: 6

Pages: 1974-1988

Print publication date: 25/09/2014

Online publication date: 18/09/2014

Acceptance date: 12/08/2014

ISSN (print): 0721-7714

ISSN (electronic): 2211-1247

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/j.celrep.2014.08.024

DOI: 10.1016/j.celrep.2014.08.024


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