Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: Down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity
Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: Down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity
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DOI：
10.1158/1078-0432.ccr-06-2294
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发表时间：
2007-04-01
影响因子：
11.5
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Hussain, Syed-Rehan A.;Cheney, Carolyn M.;Byrd, John C.
目的：抗凋亡Bcl-2家族成员蛋白Mcl-1在转化的B细胞中被动态调节，具有短的mRNA和蛋白半衰期，并且在凋亡期间被快速加工。多种治疗导致慢性和急性淋巴细胞白血病（CLL和ALL）细胞中Mcl-1的下调。Mcl-1也被报道在CLL中介导对利妥昔单抗的抗性。因此，我们调查是否直接减少的Mcl-1是足以诱导细胞凋亡和增加的敏感性rituximab.Experimental Design：我们使用Mcl-1特异性的小干扰RNA在ALL细胞系和肿瘤细胞从CLL患者阻断Mcl-1的转录。结果：我们表明，Mcl-1下调单独是足以促进线粒体膜去极化和细胞凋亡的ALL和CLL细胞。考虑到利妥昔单抗在B细胞恶性肿瘤中的重要性，我们接下来评估了Mcl-1下调对抗体介导的杀伤的影响。Mcl-1下调小干扰RNA增加利妥昔单抗介导的直接细胞凋亡和补体依赖性细胞毒性的杀伤敏感性，但没有增强抗体依赖性细胞cytotoxicity.Conclusions：这些结果表明，Mcl-1是一个相关的治疗靶点ALL和CLL，其下调有可能提高利妥昔单抗在CD 20-轴承淋巴细胞的治疗效果。
Purpose: The antiapoptotic Bcl-2 family member protein Mcl-1 is dynamically regulated in transformed B-cells, has a short mRNA and protein half-life, and is rapidly processed during apoptosis. Multiple therapies cause down-regulation of Mcl-1 in chronic and acute lymphoid leukemia (CLL and ALL) cells. Mcl-1 has also been reported to mediate resistance to rituximab in CLL. We therefore investigated whether direct reduction of Mcl-1 was sufficient to induce apoptosis and increase sensitivity to rituximab.Experimental Design: We used Mcl-1-specific small interfering RNA in ALL cell lines and tumor cells from CLL patients to block transcription of Mcl-1.Results: We show that Mcl-1 down-regulation alone is sufficient to promote mitochondrial membrane depolarization and apoptosis in ALL and CLL cells. Given the importance of rituximab in B-cell malignancies, we next assessed the influence of Mcl-1 down-regulation on antibody-mediated killing. Mcl-1 down-regulation by small interfering RNA increased sensitivity to rituximab-mediated killing both by direct apoptosis and complement-dependent cytotoxicity, but did not enhance anti body-dependent cellular cytotoxicity.Conclusions: These results show that Mcl-1 is a relevant therapeutic target for ALL and CLL, and its down-regulation has the potential to enhance the therapeutic effect of rituximab in CD20-bearing lymphoid cells.