Herold Nikolas, Rudd Sean G, Sanjiv Kumar, Kutzner Juliane, Myrberg Ida Hed, Paulin Cynthia B J, Olsen Thale Kristin, Helleday Thomas, Henter Jan-Inge, Schaller Torsten
Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden; Theme of Children's and Women's Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Exp Hematol. 2017 Aug;52:32-39. doi: 10.1016/j.exphem.2017.05.001. Epub 2017 May 11.
Sterile alpha motif and histidine/aspartic acid domain-containing protein 1 (SAMHD1) is a (deoxy)guanosine triphosphate (dGTP/GTP)-activated deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase involved in cellular dNTP homoeostasis. Mutations in SAMHD1 have been associated with the hyperinflammatory disease Aicardi-Goutières syndrome (AGS). SAMHD1 also limits cells' permissiveness to infection with diverse viruses, including human immunodeficiency virus (HIV-1), and controls endogenous retroviruses. Increasing evidence supports the role of SAMHD1 as a tumor suppressor. However, SAMHD1 also can act as a resistance factor to nucleoside-based chemotherapies by hydrolyzing their active triphosphate metabolites, thereby reducing response of various malignancies to these anticancer drugs. Hence, informed cancer therapies must take into account the ambiguous properties of SAMHD1 as both an inhibitor of uncontrolled proliferation and a resistance factor limiting the efficacy of anticancer treatments. Here, we provide evidence that SAMHD1 is a double-edged sword for patients with acute myelogenous leukemia (AML). Our time-dependent analyses of The Cancer Genome Atlas (TCGA) AML cohort indicate that high expression of SAMHD1, even though it critically limits the efficacy of high-dose ara-C therapy, might be associated with more favorable disease progression.
含无菌α基序和组氨酸/天冬氨酸结构域蛋白1（SAMHD1）是一种（脱氧）鸟苷三磷酸（dGTP/GTP）激活的脱氧核糖核苷三磷酸（dNTP）三磷酸水解酶，参与细胞dNTP稳态。SAMHD1的突变与高炎症性疾病艾卡迪-古铁雷斯综合征（AGS）相关。SAMHD1还限制细胞对包括人类免疫缺陷病毒（HIV-1）在内的多种病毒感染的易感性，并控制内源性逆转录病毒。越来越多的证据支持SAMHD1作为肿瘤抑制因子的作用。然而，SAMHD1也可通过水解核苷类化疗药物的活性三磷酸代谢产物而成为其耐药因子，从而降低各种恶性肿瘤对这些抗癌药物的反应。因此，明智的癌症治疗必须考虑到SAMHD1作为不受控制增殖的抑制剂和限制抗癌治疗疗效的耐药因子的双重特性。在此，我们提供证据表明，SAMHD1对急性髓系白血病（AML）患者来说是一把双刃剑。我们对癌症基因组图谱（TCGA）AML队列的时间依赖性分析表明，SAMHD1的高表达尽管严重限制了大剂量阿糖胞苷治疗的疗效，但可能与更有利的疾病进展相关。
