Ptasinska, A, Assi, SA, Martinez-Soria, N et al. (14 more authors) (2014) Identification of a dynamic core transcriptional network in t(8;21) AML that regulates differentiation block and self-renewal. Cell Reports, 8 (6). 1974 - 1988. ISSN 2211-1247
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | (c) 2014, The Authors. Reproduced in accordance with the publisher's self-archiving policy. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial No Derivates (CC BY-NC-ND 3.0) licence, which permits others to download this work and share it with others, provided the original work is unchanged, properly cited and the use is non-commercial. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 17 Mar 2015 10:37 |
Last Modified: | 16 Jan 2018 11:01 |
Published Version: | http://dx.doi.org/10.1016/j.celrep.2014.08.024 |
Status: | Published |
Publisher: | Elsevier |
Identification Number: | 10.1016/j.celrep.2014.08.024 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:83681 |