Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)
Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL)
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DOI：
10.1182/blood-2005-11-4465
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发表时间：
2006-05-15
期刊：
影响因子：
20.3
通讯作者：
Zauli, Giorgio
中科院分区：
文献类型：
--
作者：
Secchiero, Paola;Barbarotto, Elisa;Zauli, Giorgio
在B细胞慢性淋巴细胞白血病（B-CLL）的自然史中，p53的缺失和/或突变是相对罕见的晚期事件。然而，目前尚不清楚p53信号传导是否在B-CLL中起作用，以及通过使用nutlin-3（p53/MDM 2相互作用的小分子抑制剂）靶向非遗传毒性激活p53通路是否足以杀死B-CLL细胞。nutlin-3在体外处理诱导了对原代CD 19（+）B-CLL细胞的显著细胞毒性，但对正常CD 19 + B淋巴细胞、外周血单核细胞或骨髓造血祖细胞没有。在检查的29个B-CLL样品中，只有一个对nutlin-3介导的细胞毒性具有抗性。在B-CLL样品中nutlin-3对p53的诱导伴随着线粒体电位的改变和半胱天冬酶依赖性凋亡途径的激活。在与p53通路相关的几个基因中，nutlin-3上调PCNA、CDKN 1A/p21、GDF 15、TNFRSF 10 B/TRAIL-R2、TP 5313/PIG 3和GADD 45的稳态mRNA水平。这种基因激活的特征显示出与遗传毒性药物氟达拉滨诱导的部分重叠。此外，nutlin-3协同氟达拉滨和苯丁酸氮芥诱导B-CLL凋亡。我们的数据强烈表明，nutlin-3应进一步研究在治疗B-CLL的临床应用。
Deletions and/or mutations of p53 are relatively rare and late events in the natural history of B-cell chronic lymphocytic leukemia (B-CLL). However, it is unknown whether p53 signaling is functional in B-CLL and if targeted nongenotoxic activation of the p53 pathway by using nutlin-3, a small molecule inhibitor of the p53/MDM2 interaction, is sufficient to kill B-CLL cells. In vitro treatment with nutlin-3 induced a significant cytotoxicity on primary CD19(+) B-CLL cells, but not on normal CD19+ B lymphocytes, peripheral-blood mononuclear cells, or bone marrow hematopoietic progenitors. Among 29 B-CLL samples examined, only one was resistant to nutlin-3-mediated cytotoxicity. The induction of p53 by nutlin-3 in B-CLL samples was accompanied by alterations of the mitochondrial potential and activation of the caspase-dependent apoptotic pathway. Among several genes related to the p53 pathway, nutlin-3 up-regulated the steady-state mRNA levels of PCNA, CDKN1A/p21, GDF15,TNFRSF10B/TRAIL-R2,TP5313/PIG3, and GADD45. This profile of gene activation showed a partial overlapping with that induced by the genotoxic drug fludarabine. Moreover, nutlin-3 synergized with both fludarabine and chlorambucil in inducing B-CLL apoptosis. Our data strongly suggest that nutlin-3 should be further investigated for clinical applications in the treatment of B-CLL.