Format

Send to

Choose Destination
Nat Commun. 2019 Aug 2;10(1):3475. doi: 10.1038/s41467-019-11413-4.

Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.

Author information

1
Department of Medicine II, Hematology/Oncology, Goethe University of Frankfurt, Frankfurt, 60590, Germany.
2
German Cancer Consortium/German Cancer Research Center, Heidelberg, 69120, Germany.
3
Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt, 60596, Germany.
4
Institute of Medical Virology, University of Frankfurt, Frankfurt, 60590, Germany.
5
pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University of Frankfurt, Frankfurt, 60590, Germany.
6
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, 06520, USA.
7
Institute of Bioinformatics, University Medicine Greifswald, Greifswald, 17475, Germany.
8
Department of Medicine A, University Hospital Münster, Münster, 48149, Germany.
9
Institute of Pathology, University Medical Center, Göttingen, 37075, Germany.
10
Gerhard Domagk Institute for Pathology, University Hospital Münster, Münster, 48149, Germany.
11
Department of Haematology, Cambridge Institute of Medical Research, Cambridge University, Cambridge, CB2 0XY, UK.
12
Industrial Biotechnology Centre and School of Biosciences, University of Kent, Canterbury, CT2 7NJ, UK.
13
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project group Translational Medicine and Pharmacology (TMP), Frankfurt, 60596, Germany.
14
Institute of Medical Virology, University of Frankfurt, Frankfurt, 60590, Germany. keppler@mvp.uni-muenchen.de.
15
Max von Pettenkofer Institute, Virology, Faculty of Medicine, LMU München, Munich, 80336, Germany. keppler@mvp.uni-muenchen.de.
16
Institute of Medical Virology, University of Frankfurt, Frankfurt, 60590, Germany. Cinatl@em.uni-frankfurt.de.

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center