The deoxycytidine analogue cytarabine (ara-C) remains the backbone treatment of acute myeloid leukaemia (AML) as well as other haematological and lymphoid malignancies, but must be combined with other chemotherapeutics to achieve cure. Yet, the underlying mechanism dictating synergistic efficacy of combination chemotherapy remains largely unknown. The dNTPase SAMHD1, which regulates dNTP homoeostasis antagonistically to ribonucleotide reductase (RNR), limits ara-C efficacy by hydrolysing the active triphosphate metabolite ara-CTP. Here, we report that clinically used inhibitors of RNR, such as gemcitabine and hydroxyurea, overcome the SAMHD1-mediated barrier to ara-C efficacy in primary blasts and mouse models of AML, displaying SAMHD1-dependent synergy with ara-C. We present evidence that this is mediated by dNTP pool imbalances leading to allosteric reduction of SAMHD1 ara-CTPase activity. Thus, SAMHD1 constitutes a novel biomarker for combination therapies of ara-C and RNR inhibitors with immediate consequences for clinical practice to improve treatment of AML.

中文翻译：

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核糖核苷酸还原酶抑制剂抑制 SAMHD1 ara-CTPase 活性，增强阿糖胞苷功效。


脱氧胞苷类似物阿糖胞苷 (ara-C) 仍然是急性髓系白血病 (AML) 以及其他血液和淋巴恶性肿瘤的主要治疗方法，但必须与其他化疗药物联合使用才能治愈。然而，决定联合化疗协同功效的潜在机制仍然很大程度上未知。 dNTPase SAMHD1 与核糖核苷酸还原酶 (RNR) 拮抗地调节 dNTP 稳态，通过水解活性三磷酸代谢物 ara-CTP 来限制 ara-C 的功效。在此，我们报告临床使用的 RNR 抑制剂，如吉西他滨和羟基脲，在原发细胞和 AML 小鼠模型中克服了 SAMHD1 介导的 ara-C 功效障碍，显示出 SAMHD1 依赖的与 ara-C 的协同作用。我们提供的证据表明，这是由 dNTP 池失衡介导的，导致 SAMHD1 ara-CTPase 活性变构降低。因此，SAMHD1 构成了 ara-C 和 RNR 抑制剂联合疗法的新型生物标志物，对改善 AML 治疗的临床实践具有直接影响。