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Nat Med:德国学者揭示癌症治疗新生物标记物

摘要 : 2017年1月10日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了德国海德堡大学医院Torsten Schaller研究员的一篇研究论文,论文发现了一种新的生物标志物能够高精度检测出哪些患者会出现有效的疗效

2017年1月10日,国际学术权威刊物自然出版集团旗下子刊《Nature Medicine》杂志在线发表了德国海德堡大学医院Torsten Schaller研究员的一篇研究论文,论文发现了一种新的生物标志物能够高精度检测出哪些患者会出现有效的疗效,而哪些患者则不会,这也为目前无法得到有效治疗的患者带来了新的希望。

研究发现阿糖胞苷针对AML细胞的毒性与细胞酶SAMHD1的表达相关,后者能预测AML细胞对阿糖胞苷的敏感性。SAMHD1能去除阿糖胞苷活性形式的磷酸盐残留物,从而将其逆转成失活状态。研究人员通过与一些临床医师们的合作,进一步发现白血病细胞中的SAMHD1水平也能用于高精度预测AML患者对基于阿糖胞苷的化学疗法的反应。

由此研究人员认为将SAMHD1引入作为临床生物标志物,可以指导基于阿糖胞苷的化学疗法,发现哪些患者对这种治疗方法能产生积极的应答。此外研究人员还发现抑制SAMHD1,能有效地增加阿糖胞苷抗性AML细胞对基于阿糖胞苷化疗的敏感性,这也将为更多的患者带来新的希望,因为他们目前没有其它的有效治疗方法。

原文链接:

Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies

原文摘要:

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 adults1. 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, 3, 4, 5, which causes DNA damage through perturbation of DNA synthesis6. 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 treatment7, 8, 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.

来源: Nature Medicine 浏览次数:0

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