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 adults1. 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)2,3,4,5, which causes DNA damage through perturbation of DNA synthesis6. 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 treatment7,8,9. 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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We are grateful to M. Wickström, N. Eissler and L. Elfman for consulting and assistance with xenotransplantation. We thank S. Olsson and M. Gustafsson for assistance with animal work. We would like to thank I. Bodin for help with paraffin-embedding and processing of tumor tissue and A. Björklund for assistance with primary AML samples. We acknowledge M. Nordenskjöld and S. Eriksson for laboratory assistance, D. Gavhed and K. Edfeldt for administrative assistance. We thank D. Trono for the gift of the pMD.G plasmid. We would like to thank J. Cinatl for initial discussions. We would like to express our gratitude to NCI's Office of Cancer Genomics (OCG), The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research To Generate Effective Treatments initiative (TARGET) for granting public access to their AML databases, and to the Broad Institute for access to the Cancer Therapeutics Response Portal (CTRP). This work was supported by grants from the Swedish Children's Cancer Foundation (TJ2016-0040 (to N.H.); 2015-0005 (to J.-I.H.); PR2015-0009 (to D.G.); and PR2013-0002 and PR2014-0048 (both to T.H.)), the Swedish Cancer Society (CAN 2016/837 to J.W.; CAN 2014/814 to S.L.; CAN 2015/768 to D.G.; CAN 2013/396 to J.-I.H.; and CAN 2012/770 and CAN 2015/255 to T.H.), the Swedish Research Council (2014-1839 to M.U.; 2015-02498 to S.L.; 2012-2037 to D.G.; and 2012-5935 and 2013-3791 to T.H.), Radiumhemmet's Research Foundations (154242 to G.R. and 144063 to D.G.), the Knut and Alice Wallenberg Foundation (KAW2014.0273 to T.H.), the Swedish Pain Relief Foundation (SSF/01-05 to T.H.), the Torsten and Ragnar Söderberg Foundation (to T.H.), the David and Astrid Hagelén Foundation (C24702193 to B.D.G.P.) and the Stockholm County Council (ALF project) (20150353 to S.L. and 20150016 to J.-I.H.). This work was supported by the German Research Foundation (DFG) (SCHA1950/1-1 to T.S.) and partially through the Federal Ministry of Education and Research of Germany (BMBF)–supported Immunoquant project (0316170 C to T.S.) and HIVERA: EURECA project (01KI1307B to T.S.). S.G.R. is supported by an EMBO Long-Term Fellowship (ALTF-605-2014). Chemical Biology Consortium Sweden is funded by the Swedish Research Council, Science for Life Laboratories and Karolinska Institutet (829-2009-6241 to H.A. and T.L.).
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Enhanced Response of Acute Monocytic Leukemia Cells to Low-dose Cytarabine by 1,25-dihydroxyvitamin D3
Current Medical Science (2018)