Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies

摘要: The cytostatic deoxycytidine analog cytarabine (ara-C) is the most active agent available against acute myelogenous leukemia (AML). Together with anthracyclines, ara-C forms backbone of AML treatment for children and adults. In AML, both cytotoxicity in vitro clinical response to therapy are correlated ability blasts accumulate metabolite triphosphate (ara-CTP), which causes DNA damage through perturbation synthesis. Differences expression levels known transporters or metabolic enzymes relevant only partially account patient-specific differential ara-CTP accumulation treatment. Here we demonstrate that deoxynucleoside (dNTP) triphosphohydrolase SAM domain HD 1 (SAMHD1) promotes detoxification intracellular pools. Recombinant SAMHD1 exhibited ara-CTPase activity vitro, cells was transiently reduced by simian immunodeficiency virus (SIV) protein Vpx were dramatically more sensitive ara-C-induced cytotoxicity. CRISPR-Cas9-mediated disruption gene encoding sensitized ara-C, this sensitivity could be abrogated ectopic wild-type (WT), but not dNTPase-deficient, SAMHD1. Mouse models lacking hypersensitive ex vivo primary patient-derived ara-C. Finally, identified as a risk factor cohorts pediatric adult patients de novo who received Thus, dictate patient providing proof-of-concept targeting an attractive therapeutic strategy potentiating efficacy hematological malignancies.