Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells
Identification of TIGAR in the equilibrative nucleoside transporter 2-mediated response to fludarabine in chronic lymphocytic leukemia cells
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DOI：
10.3324/haematol.13186
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发表时间：
2008-12-01
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影响因子：
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通讯作者：
Pastor-Anglada, Marqal
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文献类型：
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作者：
Lopez-Guerra, Monica;Trigueros-Motos, Laia;Pastor-Anglada, Marqal
背景核苷类似物氟达拉滨用于治疗慢性淋巴细胞白血病。它触发p53介导的细胞凋亡，尽管p53的突变状态不能完全解释对治疗反应的异质性。本研究的目的是鉴定与氟达拉滨作用有关的新基因，以及确定平衡型核苷转运蛋白（ENT）在携带野生型p53的慢性淋巴细胞白血病细胞中由该药物触发的转录组学反应中的作用。氟达拉滨治疗的慢性淋巴细胞白血病耐药病例，无论是否存在硝基苄基硫代肌苷，hENT1特异性阻断剂。采用Taqman低密度芯片对20例慢性淋巴细胞白血病患者的细胞中20个选择的氟达拉滨诱导基因进行了验证，实验设计相同。（0132，GADD 45 A，TYMS，BAX，TIGAR，FAS，TNFSF 7，TNFSF 9，CCNG 1，CDKN 1A，MDM2，SESN 1，MAP4K4，PPM 1D，OSBPL 3和WIG 1）与慢性淋巴细胞白血病细胞对氟达拉滨的体外敏感性相关，TIGAR（TP53诱导的糖酵解和凋亡调节因子）是显示出最强相关性的基因（p
BackgroundThe nucleoside analogue fludarabine is used in the treatment of chronic lymphocytic leukemia. It triggers p53-mediated apoptosis, although the mutational status of p53 does not fully account for heterogeneity in responsiveness to treatment. The aim of this study was to identify new genes implicated in fludarabine action as well as to determine the role of equilibrative nucleoside transporters (ENT) in the transcriptomic response triggered by this drug in chronic lymphocytic leukemia cells bearing wild type p53.Design and MethodsWe performed gene expression profiling in cells from two fludarabine-sensitive and two fludarabine-resistant cases of chronic lymphocytic leukemia treated with fludarabine either in the presence or the absence of nitrobenzylthioinosine, a hENT1-specific blocker. Twenty selected fludarabine-inducible genes were validated using Taqman low-density arrays in cells from 20 chronic lymphocytic leukemia patients with the same experimental design.ResultsSixteen of the twenty genes (0132, GADD45A, TYMS, BAX, TIGAR, FAS, TNFSF7, TNFSF9, CCNG1, CDKN1A, MDM2, SESN1, MAP4K4, PPM1D, OSBPL3 and WIG1) correlated with the ex vivo sensitivity of chronic lymphocytic leukemia cells to fludarabine, TIGAR (TP53-induced glycolysis and apoptosis regulator) being the gene that showed the strongest correlation (p