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Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells

Acute promyelocytic leukemia (APL) is characterized by arrested differentiation of promyelocytes. Patients treated with all-trans retinoic acid (ATRA) alone experience relapse, while patients treated with ATRA and arsenic trioxide (ATO) are often relapse-free. This suggests sustained changes have be...

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Autores principales: Huynh, Thomas T., Sultan, Mohammad, Vidovic, Dejan, Dean, Cheryl A., Cruickshank, Brianne M., Lee, Kristen, Loung, Chao-Yu, Holloway, Ryan W., Hoskin, David W., Waisman, David M., Weaver, Ian C. G., Marcato, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602962/
https://www.ncbi.nlm.nih.gov/pubmed/31263158
http://dx.doi.org/10.1038/s41598-019-45982-7
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author Huynh, Thomas T.
Sultan, Mohammad
Vidovic, Dejan
Dean, Cheryl A.
Cruickshank, Brianne M.
Lee, Kristen
Loung, Chao-Yu
Holloway, Ryan W.
Hoskin, David W.
Waisman, David M.
Weaver, Ian C. G.
Marcato, Paola
author_facet Huynh, Thomas T.
Sultan, Mohammad
Vidovic, Dejan
Dean, Cheryl A.
Cruickshank, Brianne M.
Lee, Kristen
Loung, Chao-Yu
Holloway, Ryan W.
Hoskin, David W.
Waisman, David M.
Weaver, Ian C. G.
Marcato, Paola
author_sort Huynh, Thomas T.
collection PubMed
description Acute promyelocytic leukemia (APL) is characterized by arrested differentiation of promyelocytes. Patients treated with all-trans retinoic acid (ATRA) alone experience relapse, while patients treated with ATRA and arsenic trioxide (ATO) are often relapse-free. This suggests sustained changes have been elicited by the combination therapy. To understand the lasting effects of the combination therapy, we compared the effects of ATRA and ATO on NB4 and ATRA-resistant NB4-MR2 APL cells during treatment versus post treatment termination. After treatment termination, NB4 cells treated with ATRA or ATO reverted to non-differentiated cells, while combination-treated cells remained terminally differentiated. This effect was diminished in NB4-MR2 cells. This suggests combination treatment induced more permanent changes. Combination treatment induced higher expression of target genes (e.g., transglutaminase 2 and retinoic acid receptor beta), which in NB4 cells was sustained post treatment termination. To determine whether sustained epigenetic changes were responsible, we quantified the enrichment of histone modifications by chromatin immunoprecipitation, and CpG methylation by bisulfite-pyrosequencing. While ATRA and combination treatment induced similar histone acetylation enrichment, combination treatment induced greater demethylation of target genes, which was sustained. Therefore, sustained demethylation of target genes by ATRA and ATO combination treatment is associated with lasting differentiation and gene expression changes.
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spelling pubmed-66029622019-07-14 Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells Huynh, Thomas T. Sultan, Mohammad Vidovic, Dejan Dean, Cheryl A. Cruickshank, Brianne M. Lee, Kristen Loung, Chao-Yu Holloway, Ryan W. Hoskin, David W. Waisman, David M. Weaver, Ian C. G. Marcato, Paola Sci Rep Article Acute promyelocytic leukemia (APL) is characterized by arrested differentiation of promyelocytes. Patients treated with all-trans retinoic acid (ATRA) alone experience relapse, while patients treated with ATRA and arsenic trioxide (ATO) are often relapse-free. This suggests sustained changes have been elicited by the combination therapy. To understand the lasting effects of the combination therapy, we compared the effects of ATRA and ATO on NB4 and ATRA-resistant NB4-MR2 APL cells during treatment versus post treatment termination. After treatment termination, NB4 cells treated with ATRA or ATO reverted to non-differentiated cells, while combination-treated cells remained terminally differentiated. This effect was diminished in NB4-MR2 cells. This suggests combination treatment induced more permanent changes. Combination treatment induced higher expression of target genes (e.g., transglutaminase 2 and retinoic acid receptor beta), which in NB4 cells was sustained post treatment termination. To determine whether sustained epigenetic changes were responsible, we quantified the enrichment of histone modifications by chromatin immunoprecipitation, and CpG methylation by bisulfite-pyrosequencing. While ATRA and combination treatment induced similar histone acetylation enrichment, combination treatment induced greater demethylation of target genes, which was sustained. Therefore, sustained demethylation of target genes by ATRA and ATO combination treatment is associated with lasting differentiation and gene expression changes. Nature Publishing Group UK 2019-07-01 /pmc/articles/PMC6602962/ /pubmed/31263158 http://dx.doi.org/10.1038/s41598-019-45982-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Huynh, Thomas T.
Sultan, Mohammad
Vidovic, Dejan
Dean, Cheryl A.
Cruickshank, Brianne M.
Lee, Kristen
Loung, Chao-Yu
Holloway, Ryan W.
Hoskin, David W.
Waisman, David M.
Weaver, Ian C. G.
Marcato, Paola
Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells
title Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells
title_full Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells
title_fullStr Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells
title_full_unstemmed Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells
title_short Retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in APL cells
title_sort retinoic acid and arsenic trioxide induce lasting differentiation and demethylation of target genes in apl cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602962/
https://www.ncbi.nlm.nih.gov/pubmed/31263158
http://dx.doi.org/10.1038/s41598-019-45982-7
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