Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
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 respo...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
09 January 2017
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| In: |
Nature medicine
Year: 2017, Volume: 23, Issue: 2, Pages: 256-263 |
| ISSN: | 1546-170X |
| DOI: | 10.1038/nm.4265 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1038/nm.4265 Verlag, Volltext: https://www.nature.com/articles/nm.4265 
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| Author Notes: | Nikolas Herold, Sean G. Rudd, Linda Ljungblad, Kumar Sanjiv, Ida Hed Myrberg, Cynthia B. J. Paulin, Yaser Heshmati, Anna Hagenkort, Juliane Kutzner, Brent D.G. Page, José M. Calderón-Montaño, Olga Loseva, Ann-Sofie Jemth, Lorenzo Bulli, Hanna Axelsson, Bianca Tesi, Nicholas C.K. Valerie, Andreas Höglund, Julia Bladh, Elisée Wiita, Mikael Sundin, Michael Uhlin, Georgios Rassidakis, Mats Heyman, Katja Pokrovskaja Tamm, Ulrika Warpman-Berglund, Julian Walfridsson, Sören Lehmann, Dan Grandér, Thomas Lundbäck, Per Kogner, Jan-Inge Henter, Thomas Helleday & Torsten Schaller |
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| 520 | |a 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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