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 bioma
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.
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Metadaten
Author:Thomas Oellerich, Constanze Schneider, Dominique Jeanette Thomas, Kirsten M. Knecht, Olga Buzovetsky, Lars Kaderali, Christoph Schliemann, Hanibal Bohnenberger, Linus Angenendt, Wolfgang Hartmann, Eva Wardelmann, Tamara Rothenburger, Sebastian Mohr, Sebastian Scheich, Federico Comoglio, Anne Wilke, Philipp Ströbel, Hubert Serve, Martin Michaelis, Nerea Ferreirós Bouzas, Gerd Geisslinger, Yong Xiong, Oliver Till Keppler, Jindrich Cinatl
URN:urn:nbn:de:hebis:30:3-507543
DOI:http://dx.doi.org/10.1038/s41467-019-11413-4
ISSN:2041-1723
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=31375673
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group UK
Place of publication:[London]
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/08/02
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/08/19
Tag:Biomarkers; Cancer; Oncology
Volume:10
Issue:1, Art. 3475
Pagenumber:14
First Page:1
Last Page:14
Note:
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/.
HeBIS PPN:453739636
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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