SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia
SAMHD1 is a biomarker for cytarabine response and a therapeutic target in acute myeloid leukemia
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DOI：
10.1038/nm.4255
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发表时间：
2017-02-01
期刊：
影响因子：
82.9
通讯作者：
Cinatl, Jindrich, Jr.
中科院分区：
文献类型：
--
作者：
Schneider, Constanze;Oellerich, Thomas;Cinatl, Jindrich, Jr.
核苷类似物阿糖胞苷（Ara-C）是急性髓性白血病（AML）的主要和补救化疗方案的重要组成部分。细胞摄取后，Ara-C转化为具有治疗活性的三磷酸代谢物Ara-CTP，其主要通过抑制增殖细胞中的DNA合成发挥抗白血病作用。目前，很大一部分AML患者对Ara-C治疗无效，并且缺乏预测Ara-C治疗反应的可靠生物标志物（2，3）。SAMHD 1是一种脱氧核苷三磷酸（dNTP）三磷酸水解酶，可将生理性dNTP切割成脱氧核糖核苷和无机三磷酸（4，5）。尽管已经假设SAMHD 1通过耗尽竞争性dNTPs 6使癌细胞对核苷类似物衍生物敏感，但我们在此表明SAMHD 1降低AML细胞中的Ara-C细胞毒性。从机制上讲，dGTP激活的SAMHD 1水解Ara-CTP，导致白血病细胞中Ara-CTP的急剧减少。SAMHD 1活性的丧失通过基因耗竭、其三磷酸水解酶活性的突变失活或使用专门的病毒样颗粒的蛋白酶体降解（7，8）增强Ara-C在AML细胞中的细胞毒性。在逆转录病毒AML移植的小鼠模型中，以及在AML成人患者的回顾性分析中，对含Ara-C治疗的反应与SAMHD 1表达呈负相关。这些结果将SAMHD 1确定为可能对基于Ara-C的治疗反应最好的AML患者分层的潜在生物标志物，并作为治疗Ara-C难治性AML的靶点。
The nucleoside analog cytarabine (Ara-C) is an essential component of primary and salvage chemotherapy regimens for acute myeloid leukemia (AML). After cellular uptake, Ara-C is converted into its therapeutically active triphosphate metabolite, Ara-CTP, which exerts antileukemic effects, primarily by inhibiting DNA synthesis in proliferating cells'. Currently, a substantial fraction of patients with AML fail to respond effectively to Ara-C therapy, and reliable biomarkers for predicting the therapeutic response to Ara-C are lacking(2,3). SAMHD1 is a deoxynucleoside triphosphate (dNTP) triphosphohydrolase that cleaves physiological dNTPs into deoxyribonucleosides and inorganic triphosphate(4,5). Although it has been postulated that SAMHD1 sensitizes cancer cells to nucleoside-analog derivatives through the depletion of competing dNTPs6, we show here that SAMHD1 reduces Ara-C cytotoxicity in AML cells. Mechanistically, dGTP-activated SAMHD1 hydrolyzes Ara-CTP, which results in a drastic reduction of Ara-CTP in leukemic cells. Loss of SAMHD1 activity through genetic depletion, mutational inactivation of its triphosphohydrolase activity or proteasomal degradation using specialized, virus-like particles(7,8) potentiates the cytotoxicity of Ara-C in AML cells. In mouse models of retroviral AML transplantation, as well as in retrospective analyses of adult patients with AML, the response to Ara-C-containing therapy was inversely correlated with SAMHD1 expression. These results identify SAMHD1 as a potential biomarker for the stratification of patients with AML who might best respond to Ara-C-based therapy and as a target for treating Ara-C-refractory AML.