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The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation
The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all-trans...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395383/ https://www.ncbi.nlm.nih.gov/pubmed/35995769 http://dx.doi.org/10.1038/s41408-022-00715-4 |
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author | Meier, Ruth Greve, Gabriele Zimmer, Dennis Bresser, Helena Berberich, Bettina Langova, Ralitsa Stomper, Julia Rubarth, Anne Feuerbach, Lars Lipka, Daniel B. Hey, Joschka Grüning, Björn Brors, Benedikt Duyster, Justus Plass, Christoph Becker, Heiko Lübbert, Michael |
author_facet | Meier, Ruth Greve, Gabriele Zimmer, Dennis Bresser, Helena Berberich, Bettina Langova, Ralitsa Stomper, Julia Rubarth, Anne Feuerbach, Lars Lipka, Daniel B. Hey, Joschka Grüning, Björn Brors, Benedikt Duyster, Justus Plass, Christoph Becker, Heiko Lübbert, Michael |
author_sort | Meier, Ruth |
collection | PubMed |
description | The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all-trans retinoic acid (ATRA) resulted in an improved response rate and longer overall survival in a randomized phase II trial (DECIDER; NCT00867672). The molecular mechanisms governing this in vivo synergism are unclear. We now demonstrate cooperative antileukemic effects of DAC and ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, derepression of >1200 commonly regulated transcripts following the dual treatment was observed. Overall chromatin accessibility (interrogated by ATAC-seq) and, in particular, at motifs of retinoic acid response elements were affected by both single-agent DAC and ATRA, and enhanced by the dual treatment. Cooperativity regarding transcriptional induction and chromatin remodeling was demonstrated by interrogating the HIC1, CYP26A1, GBP4, and LYZ genes, in vivo gene derepression by expression studies on peripheral blood blasts from AML patients receiving DAC + ATRA. The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53) than MOLM-13 (intact TP53), resulting in a “viral mimicry” response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA. |
format | Online Article Text |
id | pubmed-9395383 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93953832022-08-24 The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation Meier, Ruth Greve, Gabriele Zimmer, Dennis Bresser, Helena Berberich, Bettina Langova, Ralitsa Stomper, Julia Rubarth, Anne Feuerbach, Lars Lipka, Daniel B. Hey, Joschka Grüning, Björn Brors, Benedikt Duyster, Justus Plass, Christoph Becker, Heiko Lübbert, Michael Blood Cancer J Article The prognosis of AML patients with adverse genetics, such as a complex, monosomal karyotype and TP53 lesions, is still dismal even with standard chemotherapy. DNA-hypomethylating agent monotherapy induces an encouraging response rate in these patients. When combined with decitabine (DAC), all-trans retinoic acid (ATRA) resulted in an improved response rate and longer overall survival in a randomized phase II trial (DECIDER; NCT00867672). The molecular mechanisms governing this in vivo synergism are unclear. We now demonstrate cooperative antileukemic effects of DAC and ATRA on AML cell lines U937 and MOLM-13. By RNA-sequencing, derepression of >1200 commonly regulated transcripts following the dual treatment was observed. Overall chromatin accessibility (interrogated by ATAC-seq) and, in particular, at motifs of retinoic acid response elements were affected by both single-agent DAC and ATRA, and enhanced by the dual treatment. Cooperativity regarding transcriptional induction and chromatin remodeling was demonstrated by interrogating the HIC1, CYP26A1, GBP4, and LYZ genes, in vivo gene derepression by expression studies on peripheral blood blasts from AML patients receiving DAC + ATRA. The two drugs also cooperated in derepression of transposable elements, more effectively in U937 (mutated TP53) than MOLM-13 (intact TP53), resulting in a “viral mimicry” response. In conclusion, we demonstrate that in vitro and in vivo, the antileukemic and gene-derepressive epigenetic activity of DAC is enhanced by ATRA. Nature Publishing Group UK 2022-08-22 /pmc/articles/PMC9395383/ /pubmed/35995769 http://dx.doi.org/10.1038/s41408-022-00715-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Meier, Ruth Greve, Gabriele Zimmer, Dennis Bresser, Helena Berberich, Bettina Langova, Ralitsa Stomper, Julia Rubarth, Anne Feuerbach, Lars Lipka, Daniel B. Hey, Joschka Grüning, Björn Brors, Benedikt Duyster, Justus Plass, Christoph Becker, Heiko Lübbert, Michael The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation |
title | The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation |
title_full | The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation |
title_fullStr | The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation |
title_full_unstemmed | The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation |
title_short | The antileukemic activity of decitabine upon PML/RARA-negative AML blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation |
title_sort | antileukemic activity of decitabine upon pml/rara-negative aml blasts is supported by all-trans retinoic acid: in vitro and in vivo evidence for cooperation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9395383/ https://www.ncbi.nlm.nih.gov/pubmed/35995769 http://dx.doi.org/10.1038/s41408-022-00715-4 |
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