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

Schneider, Constanze, Oellerich, Thomas, Baldauf, Hanna-Mari, Schwarz, Sarah-Marie, Thomas, Dominique, Flick, Robert, Bohnenberger, Hanibal, Kaderali, Lars, Stegmann, Lena, Cremer, Anjali, and others. (2016) SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia. Nature medicine, 23 (2). pp. 250-255. ISSN 1078-8956. E-ISSN 1546-170X. (doi:10.1038/nm.4255) (KAR id:60380)

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Official URL: http://dx.doi.org/10.1038/nm.4255

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.

Item Type:	Article
DOI/Identification number:	10.1038/nm.4255
Subjects:	R Medicine > RM Therapeutics. Pharmacology
Divisions:	Divisions > Division of Natural Sciences > Biosciences
Depositing User:	Martin Michaelis
Date Deposited:	15 Feb 2017 10:58 UTC
Last Modified:	05 Nov 2024 10:53 UTC
Resource URI:	https://kar.kent.ac.uk/id/eprint/60380 (The current URI for this page, for reference purposes)

University of Kent Author Information

Michaelis, Martin.

Creator's ORCID:	https://orcid.org/0000-0002-5710-5888
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