SAMHD1通过保护细胞免受dGTP的细胞毒性作用，限制了福达司他在白血病中的疗效。

SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP.

作者信息

Davenne Tamara, Klintman Jenny, Sharma Sushma, Rigby Rachel E, Blest Henry T W, Cursi Chiara, Bridgeman Anne, Dadonaite Bernadeta, De Keersmaecker Kim, Hillmen Peter, Chabes Andrei, Schuh Anna, Rehwinkel Jan

机构信息

Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; Laboratory for Disease Mechanisms in Cancer, Department of Oncology, KU Leuven and Leuven Cancer Institute (LKI), Herestraat 49, 3000 Leuven, Belgium.

Molecular Diagnostic Centre, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.

出版信息

Cell Rep. 2020 May 12;31(6):107640. doi: 10.1016/j.celrep.2020.107640.

The anti-leukemia agent forodesine causes cytotoxic overload of intracellular deoxyguanosine triphosphate (dGTP) but is efficacious only in a subset of patients. We report that SAMHD1, a phosphohydrolase degrading deoxyribonucleoside triphosphate (dNTP), protects cells against the effects of dNTP imbalances. SAMHD1-deficient cells induce intrinsic apoptosis upon provision of deoxyribonucleosides, particularly deoxyguanosine (dG). Moreover, dG and forodesine act synergistically to kill cells lacking SAMHD1. Using mass cytometry, we find that these compounds kill SAMHD1-deficient malignant cells in patients with chronic lymphocytic leukemia (CLL). Normal cells and CLL cells from patients without SAMHD1 mutation are unaffected. We therefore propose to use forodesine as a precision medicine for leukemia, stratifying patients by SAMHD1 genotype or expression.

抗白血病药物福达华会导致细胞内三磷酸脱氧鸟苷（dGTP）的细胞毒性过载，但仅对一部分患者有效。我们报告称，SAMHD1是一种降解三磷酸脱氧核糖核苷（dNTP）的磷酸水解酶，可保护细胞免受dNTP失衡的影响。缺乏SAMHD1的细胞在提供脱氧核苷，特别是脱氧鸟苷（dG）后会诱导内源性凋亡。此外，dG和福达华协同作用杀死缺乏SAMHD1的细胞。使用质谱流式细胞术，我们发现这些化合物可杀死慢性淋巴细胞白血病（CLL）患者中缺乏SAMHD1的恶性细胞。来自无SAMHD1突变患者的正常细胞和CLL细胞不受影响。因此，我们建议将福达华用作白血病的精准药物，根据SAMHD1基因型或表达对患者进行分层。