Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal
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-...
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| Format: | Online |
| Language: | English |
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Cell Press
2014
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487811/ |
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pubmed-4487811 |
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oai_dc |
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pubmed-44878112015-07-01 Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal 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 Bonifer, Constanze Article 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. Cell Press 2014-09-18 /pmc/articles/PMC4487811/ /pubmed/25242324 http://dx.doi.org/10.1016/j.celrep.2014.08.024 Text en © 2014 The Authors http://creativecommons.org/licenses/by-nc-nd/3.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
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 Bonifer, Constanze |
| spellingShingle |
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 Bonifer, Constanze Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal |
| author_facet |
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 Bonifer, Constanze |
| author_sort |
Ptasinska, Anetta |
| title |
Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal |
| title_short |
Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal |
| title_full |
Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal |
| title_fullStr |
Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal |
| title_full_unstemmed |
Identification of a Dynamic Core Transcriptional Network in t(8;21) AML that Regulates Differentiation Block and Self-Renewal |
| title_sort |
identification of a dynamic core transcriptional network in t(8;21) aml that regulates differentiation block and self-renewal |
| description |
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. |
| publisher |
Cell Press |
| publishDate |
2014 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487811/ |
| _version_ |
1613242390038970368 |