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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, and others. (2019) Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML. Nature Communications, 10 (1). Article Number 3475. ISSN 2041-1723. (doi:10.1038/s41467-019-11413-4) (KAR id:76171)

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https://doi.org/10.1038/s41467-019-11413-4

Abstract

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.

Item Type: Article
DOI/Identification number: 10.1038/s41467-019-11413-4
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Divisions > Division of Natural Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 04 Sep 2019 08:41 UTC
Last Modified: 16 Oct 2020 13:10 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/76171 (The current URI for this page, for reference purposes)
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
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