SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine
复制标题
DOI：
10.1038/s42003-020-1052-8
复制
发表时间：
2020-06-24
影响因子：
5.9
通讯作者：
Cinatl, Jindrich, Jr.
中科院分区：
文献类型：
--
作者：
Rothenburger, Tamara;McLaughlin, Katie-May;Cinatl, Jindrich, Jr.
核苷类似物奈拉滨是阿拉伯糖基鸟嘌呤（AraG）的前药，对T细胞急性淋巴细胞白血病（T-ALL）有效，但对B细胞ALL（B-ALL）无效。其内在机制仍然难以捉摸。在这里，来自药物基因组学研究和一组ALL细胞系的数据揭示了奈拉滨敏感性和SAMHD 1表达之间的负相关性，SAMHD 1可以水解和水解三磷酸化核苷类似物。在细胞系和患者来源的白血病母细胞中，在T-ALL中检测到的SAMHD 1丰度低于B-ALL。从机制上讲，T-ALL细胞显示SAMHD 1启动子甲基化增加，而没有增加整体DNA甲基化。SAMHD 1缺失使B-ALL细胞对AraG敏感，而SAMHD 1缺失的T-ALL细胞中的异位SAMHD 1表达诱导AraG抗性。在ALL细胞中，SAMHD 1对奈拉滨/AraG的影响大于对阿糖胞苷的影响。在急性髓性白血病细胞中观察到相反的效果，表明实体特异性差异。总之，SAMHD 1启动子甲基化和SAMHD 1表达水平决定了ALL细胞对奈拉滨的反应。Rothenburger et al.联合收割机将大型药物基因组学筛选数据分析与细胞系实验相结合，以阐明急性淋巴细胞白血病（ALL）中奈拉滨耐药背后的机制。他们鉴定了dNTP水解酶SAMHD 1的低表达作为奈拉滨敏感性的决定因素，表明该酶作为生物标志物。
The nucleoside analogue nelarabine, the prodrug of arabinosylguanine (AraG), is effective against T-cell acute lymphoblastic leukaemia (T-ALL) but not against B-cell ALL (B-ALL). The underlying mechanisms have remained elusive. Here, data from pharmacogenomics studies and a panel of ALL cell lines reveal an inverse correlation between nelarabine sensitivity and the expression of SAMHD1, which can hydrolyse and inactivate triphosphorylated nucleoside analogues. Lower SAMHD1 abundance is detected in T-ALL than in B-ALL in cell lines and patient-derived leukaemic blasts. Mechanistically, T-ALL cells display increased SAMHD1 promoter methylation without increased global DNA methylation. SAMHD1 depletion sensitises B-ALL cells to AraG, while ectopic SAMHD1 expression in SAMHD1-null T-ALL cells induces AraG resistance. SAMHD1 has a larger impact on nelarabine/AraG than on cytarabine in ALL cells. Opposite effects are observed in acute myeloid leukaemia cells, indicating entity-specific differences. In conclusion, SAMHD1 promoter methylation and, in turn, SAMHD1 expression levels determine ALL cell response to nelarabine. Rothenburger et al. combine the analysis of data from large pharmacogenomics screens with cell line experiments to elucidate mechanisms behind nelarabine resistance in acute lymphoblastic leukaemia (ALL). They identify low expression of the dNTP hydrolase SAMHD1 as a determinant of nelarabine sensitivity, suggesting the enzyme as a biomarker.