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Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding

The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiati...

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Autores principales: Ptasinska, A, Assi, S A, Mannari, D, James, S R, Williamson, D, Dunne, J, Hoogenkamp, M, Wu, M, Care, M, McNeill, H, Cauchy, P, Cullen, M, Tooze, R M, Tenen, D G, Young, B D, Cockerill, P N, Westhead, D R, Heidenreich, O, Bonifer, C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419980/
https://www.ncbi.nlm.nih.gov/pubmed/22343733
http://dx.doi.org/10.1038/leu.2012.49
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author Ptasinska, A
Assi, S A
Mannari, D
James, S R
Williamson, D
Dunne, J
Hoogenkamp, M
Wu, M
Care, M
McNeill, H
Cauchy, P
Cullen, M
Tooze, R M
Tenen, D G
Young, B D
Cockerill, P N
Westhead, D R
Heidenreich, O
Bonifer, C
author_facet Ptasinska, A
Assi, S A
Mannari, D
James, S R
Williamson, D
Dunne, J
Hoogenkamp, M
Wu, M
Care, M
McNeill, H
Cauchy, P
Cullen, M
Tooze, R M
Tenen, D G
Young, B D
Cockerill, P N
Westhead, D R
Heidenreich, O
Bonifer, C
author_sort Ptasinska, A
collection PubMed
description The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML.
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spelling pubmed-34199802012-08-16 Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding Ptasinska, A Assi, S A Mannari, D James, S R Williamson, D Dunne, J Hoogenkamp, M Wu, M Care, M McNeill, H Cauchy, P Cullen, M Tooze, R M Tenen, D G Young, B D Cockerill, P N Westhead, D R Heidenreich, O Bonifer, C Leukemia Original Article The t(8;21) translocation fuses the DNA-binding domain of the hematopoietic master regulator RUNX1 to the ETO protein. The resultant RUNX1/ETO fusion protein is a leukemia-initiating transcription factor that interferes with RUNX1 function. The result of this interference is a block in differentiation and, finally, the development of acute myeloid leukemia (AML). To obtain insights into RUNX1/ETO-dependant alterations of the epigenetic landscape, we measured genome-wide RUNX1- and RUNX1/ETO-bound regions in t(8;21) cells and assessed to what extent the effects of RUNX1/ETO on the epigenome depend on its continued expression in established leukemic cells. To this end, we determined dynamic alterations of histone acetylation, RNA Polymerase II binding and RUNX1 occupancy in the presence or absence of RUNX1/ETO using a knockdown approach. Combined global assessments of chromatin accessibility and kinetic gene expression data show that RUNX1/ETO controls the expression of important regulators of hematopoietic differentiation and self-renewal. We show that selective removal of RUNX1/ETO leads to a widespread reversal of epigenetic reprogramming and a genome-wide redistribution of RUNX1 binding, resulting in the inhibition of leukemic proliferation and self-renewal, and the induction of differentiation. This demonstrates that RUNX1/ETO represents a pivotal therapeutic target in AML. Nature Publishing Group 2012-08 2012-03-16 /pmc/articles/PMC3419980/ /pubmed/22343733 http://dx.doi.org/10.1038/leu.2012.49 Text en Copyright © 2012 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
spellingShingle Original Article
Ptasinska, A
Assi, S A
Mannari, D
James, S R
Williamson, D
Dunne, J
Hoogenkamp, M
Wu, M
Care, M
McNeill, H
Cauchy, P
Cullen, M
Tooze, R M
Tenen, D G
Young, B D
Cockerill, P N
Westhead, D R
Heidenreich, O
Bonifer, C
Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding
title Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding
title_full Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding
title_fullStr Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding
title_full_unstemmed Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding
title_short Depletion of RUNX1/ETO in t(8;21) AML cells leads to genome-wide changes in chromatin structure and transcription factor binding
title_sort depletion of runx1/eto in t(8;21) aml cells leads to genome-wide changes in chromatin structure and transcription factor binding
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419980/
https://www.ncbi.nlm.nih.gov/pubmed/22343733
http://dx.doi.org/10.1038/leu.2012.49
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