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Nat Med. 2017 Feb;23(2):250-255. doi: 10.1038/nm.4255. Epub 2016 Dec 19.

SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia.

Author information

1
Institute of Medical Virology, University of Frankfurt, Frankfurt, Germany.
2
Department of Medicine II, Hematology and Oncology, Goethe University of Frankfurt, Frankfurt, Germany.
3
Cambridge University Department of Haematology, Cambridge Institute of Medical Research, Cambridge, UK.
4
German Cancer Consortium partner site, German Cancer Research Center, Heidelberg, Germany.
5
Max von Pettenkofer Institute, Department of Virology, Ludwig Maximilian University of Munich, Munich, Germany.
6
Pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe University of Frankfurt, Frankfurt, Germany.
7
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Canada.
8
Institute of Pathology, University Medical Center, Göttingen, Germany.
9
Institute of Bioinformatics, University Medicine Greifswald, Greifswald, Germany.
10
Centre for Molecular Processing and School of Biosciences, University of Kent, Canterbury, UK.
11
Institute of Molecular Medicine, University Hospital Bonn, Bonn, Germany.
12
Gene Center and Department of Biochemistry, Ludwig Maximilian University of Munich, Munich, Germany.
13
Department of Medicine A (Hematology, Oncology), University Hospital Münster, Germany.
14
Gerhard Domagk Institute for Pathology, University Hospital Münster, Germany.
15
Senckenberg Institute of Pathology, University of Frankfurt, Frankfurt, Germany.
16
Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Project Group Translational Medicine and Pharmacology (TMP), Frankfurt, Germany.

Abstract

The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking. SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate. Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity-through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles-potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.

PMID:
27991919
DOI:
10.1038/nm.4255
[Indexed for MEDLINE]

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