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Identification of a dynamic core transcriptional network in t(8;21) AML that regulates Differentiation block and self-renewal
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Ptasinska, Anetta, Assi, Salam A., Martinez-Soria, Natalia, Imperato, Maria Rosaria, Piper, Jason, Cauchy, Pierre, Pickin, Anna, James, Sally R., Hoogenkamp, Maarten, Williamson, Dan, Wu, Mengchu, Tenen, Daniel G., Ott, Sascha, Westhead, David R., Cockerill, Peter N., Heidenreich, Olaf and Bonifer, Constanze (2014) Identification of a dynamic core transcriptional network in t(8;21) AML that regulates Differentiation block and self-renewal. Cell Reports, 8 (6). pp. 1974-1988. 24. doi:10.1016/j.celrep.2014.08.024
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Official URL: http://dx.doi.org/10.1016/j.celrep.2014.08.024
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.
| Item Type: | Journal Article | ||||||||||
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| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Research Centres > Warwick Systems Biology Centre | ||||||||||
| Library of Congress Subject Headings (LCSH): | Cancer, Oncology, Leukemia, Experimental | ||||||||||
| Journal or Publication Title: | Cell Reports | ||||||||||
| Publisher: | Elsevier Inc. | ||||||||||
| ISSN: | 2211-1247 | ||||||||||
| Official Date: | 25 September 2014 | ||||||||||
| Dates: |
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| Volume: | 8 | ||||||||||
| Number: | 6 | ||||||||||
| Page Range: | pp. 1974-1988 | ||||||||||
| Article Number: | 24 | ||||||||||
| DOI: | 10.1016/j.celrep.2014.08.024 | ||||||||||
| Status: | Peer Reviewed | ||||||||||
| Publication Status: | Published | ||||||||||
| Access rights to Published version: | Open Access | ||||||||||
| Funder: | Leukaemia & Lymphoma Research (LLR), Medical Research Council, UK, North of England Children’s Cancer Fund | ||||||||||
| Grant number: | 7001, 12007, 10033, 12055 |
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