Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies
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DOI：
10.1038/nm.4265
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发表时间：
2017-02-01
期刊：
影响因子：
82.9
通讯作者：
Schaller, Torsten
中科院分区：
文献类型：
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作者：
Herold, Nikolas;Rudd, Sean G.;Schaller, Torsten
细胞生长抑制性脱氧胞苷类似物阿糖胞苷（ara-C）是目前治疗急性髓细胞性白血病（AML）最有效的药物。与蒽环类药物一起，阿糖胞苷构成了儿童和成人AML治疗的支柱。在AML中，阿糖胞苷的体外细胞毒性和对阿糖胞苷治疗的临床反应均与AML母细胞积累活性代谢物三磷酸阿糖胞苷（ara-CTP）的能力相关（2-5），其通过干扰DNA合成导致DNA损伤（6）。与ara-C相关的已知转运蛋白或代谢酶的表达水平的差异仅部分解释了AML原始细胞中患者特异性差异ara-CTP积累和对ara-C治疗的应答（7-9）。在这里，我们证明了脱氧核苷三磷酸（dNTP）三磷酸水解酶SAM结构域和HD结构域1（SAMHD 1）促进细胞内ara-CTP池的解毒。重组SAMHD 1在体外表现出阿糖胞苷的活性，并且通过用猴免疫缺陷病毒（SIV）蛋白Vpx处理而暂时降低SAMHD 1表达的细胞对阿糖胞苷诱导的细胞毒性显著更敏感。CRISPR-Cas9介导的编码SAMHD 1的基因的破坏使细胞对ara-C敏感，并且这种敏感性可以通过野生型（WT）而不是dNTPase-deficient的SAMHD 1的异位表达来消除。缺乏SAMHD 1的AML小鼠模型对阿糖胞苷过敏，用Vpx离体治疗使原发性患者来源的AML母细胞对阿糖胞苷敏感。最后，我们确定SAMHD 1是接受阿糖胞苷治疗的儿童和成人初发AML患者队列的风险因素。因此，SAMHD 1表达水平决定了患者对阿糖胞苷的敏感性，提供了概念验证，即Vpx靶向SAMHD 1可能是一种有吸引力的治疗策略，用于增强阿糖胞苷在血液恶性肿瘤中的疗效。
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.