Journal
NATURE MEDICINE
Volume 23, Issue 2, Pages 256-263Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4265
Keywords
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Funding
- Swedish Children's Cancer Foundation [TJ2016-0040, 2015-0005, PR2015-0009, PR2013-0002, PR2014-0048]
- Swedish Cancer Society [CAN 2016/837, CAN 2014/814, CAN 2015/768, CAN 2013/396, CAN 2012/770, CAN 2015/255]
- Swedish Research Council [2014-1839, 2015-02498, 2012-2037, 2012-5935, 2013-3791]
- Radiumhemmet's Research Foundations [154242, 144063]
- Knut and Alice Wallenberg Foundation [KAW2014.0273]
- Swedish Pain Relief Foundation [SSF/01-05]
- Torsten and Ragnar Soderberg Foundation
- David and Astrid Hagelen Foundation [C24702193]
- Stockholm County Council (ALF project) [20150353, 20150016]
- German Research Foundation (DFG) [SCHA1950/1-1]
- Federal Ministry of Education and Research of Germany (BMBF) [0316170]
- HIVERA: EURECA project [01KI1307B]
- EMBO Long-Term Fellowship [ALTF-605-2014]
- Swedish Research Council, Science for Life Laboratories and Karolinska Institutet [829-2009-6241]
- Swedish Research Council [2015-02498] Funding Source: Swedish Research Council
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The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms the backbone of AML treatment for children and adults'. In AML, both the cytotoxicity of ara-C in vitro and the clinical response to ara-C therapy are correlated with the ability of AML blasts to accumulate the active metabolite ara-C triphosphate (ara-CTP)(2-5), which causes DNA damage through perturbation of DNA synthesis(6). Differences in expression levels of known transporters or metabolic enzymes relevant to ara-C only partially account for patient-specific differential ara-CTP accumulation in AML blasts and response to ara-C treatment(7-9). Here we demonstrate that the deoxynucleoside triphosphate (dNTP) triphosphohydrolase SAM domain and HD domain 1 (SAMHD1) promotes the detoxification of intracellular ara-CTP pools. Recombinant SAMHD1 exhibited ara-CTPase activity in vitro, and cells in which SAMHD1 expression was transiently reduced by treatment with the simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive to ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption of the gene encoding SAMHD1 sensitized cells to ara-C, and this sensitivity could be abrogated by ectopic expression of wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models of AML lacking SAMHD1 were hypersensitive to ara-C, and treatment ex vivo with Vpx sensitized primary patient derived AML blasts to ara-C. Finally, we identified SAMHD1 as a risk factor in cohorts of both pediatric and adult patients with de novo AML who received ara-C treatment. Thus, SAMHD1 expression levels dictate patient sensitivity to ara-C, providing proof-of-concept that the targeting of SAMHD1 by Vpx could be an attractive therapeutic strategy for potentiating ara-C efficacy in hematological malignancies.
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