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Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML
Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677770/ https://www.ncbi.nlm.nih.gov/pubmed/31375673 http://dx.doi.org/10.1038/s41467-019-11413-4 |
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author | Oellerich, Thomas Schneider, Constanze Thomas, Dominique Knecht, Kirsten M. Buzovetsky, Olga Kaderali, Lars Schliemann, Christoph Bohnenberger, Hanibal Angenendt, Linus Hartmann, Wolfgang Wardelmann, Eva Rothenburger, Tamara Mohr, Sebastian Scheich, Sebastian Comoglio, Federico Wilke, Anne Ströbel, Philipp Serve, Hubert Michaelis, Martin Ferreirós, Nerea Geisslinger, Gerd Xiong, Yong Keppler, Oliver T. Cinatl, Jindrich |
author_facet | Oellerich, Thomas Schneider, Constanze Thomas, Dominique Knecht, Kirsten M. Buzovetsky, Olga Kaderali, Lars Schliemann, Christoph Bohnenberger, Hanibal Angenendt, Linus Hartmann, Wolfgang Wardelmann, Eva Rothenburger, Tamara Mohr, Sebastian Scheich, Sebastian Comoglio, Federico Wilke, Anne Ströbel, Philipp Serve, Hubert Michaelis, Martin Ferreirós, Nerea Geisslinger, Gerd Xiong, Yong Keppler, Oliver T. Cinatl, Jindrich |
author_sort | Oellerich, Thomas |
collection | PubMed |
description | Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia. |
format | Online Article Text |
id | pubmed-6677770 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66777702019-08-05 Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML Oellerich, Thomas Schneider, Constanze Thomas, Dominique Knecht, Kirsten M. Buzovetsky, Olga Kaderali, Lars Schliemann, Christoph Bohnenberger, Hanibal Angenendt, Linus Hartmann, Wolfgang Wardelmann, Eva Rothenburger, Tamara Mohr, Sebastian Scheich, Sebastian Comoglio, Federico Wilke, Anne Ströbel, Philipp Serve, Hubert Michaelis, Martin Ferreirós, Nerea Geisslinger, Gerd Xiong, Yong Keppler, Oliver T. Cinatl, Jindrich Nat Commun Article Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia. Nature Publishing Group UK 2019-08-02 /pmc/articles/PMC6677770/ /pubmed/31375673 http://dx.doi.org/10.1038/s41467-019-11413-4 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 Oellerich, Thomas Schneider, Constanze Thomas, Dominique Knecht, Kirsten M. Buzovetsky, Olga Kaderali, Lars Schliemann, Christoph Bohnenberger, Hanibal Angenendt, Linus Hartmann, Wolfgang Wardelmann, Eva Rothenburger, Tamara Mohr, Sebastian Scheich, Sebastian Comoglio, Federico Wilke, Anne Ströbel, Philipp Serve, Hubert Michaelis, Martin Ferreirós, Nerea Geisslinger, Gerd Xiong, Yong Keppler, Oliver T. Cinatl, Jindrich Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML |
title | Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML |
title_full | Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML |
title_fullStr | Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML |
title_full_unstemmed | Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML |
title_short | Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML |
title_sort | selective inactivation of hypomethylating agents by samhd1 provides a rationale for therapeutic stratification in aml |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677770/ https://www.ncbi.nlm.nih.gov/pubmed/31375673 http://dx.doi.org/10.1038/s41467-019-11413-4 |
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