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可抑制SAMHD1 ara-CTPase活性，从而增强阿糖胞苷的疗效。

脱氧胞苷类似物阿糖胞苷（ara-C）仍然是急性髓细胞性白血病（AML）以及其他血液学和淋巴性恶性肿瘤的主要治疗手段，但必须与其他化疗药物结合才能治愈。然而，决定联合化疗协同疗效的潜在机制仍是未知之数。dNTPase SAMHD1与核糖核苷酸还原酶（RNR）拮抗地调节dNTP的稳态，通过水解活性三磷酸代谢物ara-CTP限制ara-C的功效。在这里，我们报告临床上使用的RNR抑制剂，如吉西他滨和羟基脲，克服了AML的原代和小鼠模型中SAMHD1介导的对ara-C功效的障碍，显示了与ara-C的SAMHD1依赖性协同作用。我们目前的证据，这是由dNTP池失衡介导的，导致SAMHD1 ara-CTPase活性的变构降低。因此，SAMHD1构成了ara-C和RNR抑制剂联合治疗的新型生物标志物，对改善AML的临床实践具有直接影响。