Hussain Syed-Rehan A, Cheney Carolyn M, Johnson Amy J, Lin Thomas S, Grever Michael R, Caligiuri Michael A, Lucas David M, Byrd John C
Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Clin Cancer Res. 2007 Apr 1;13(7):2144-50. doi: 10.1158/1078-0432.CCR-06-2294.
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.
We used Mcl-1-specific small interfering RNA in ALL cell lines and tumor cells from CLL patients to block transcription of Mcl-1.
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 antibody-dependent cellular cytotoxicity.
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.
抗凋亡的Bcl-2家族成员蛋白Mcl-1在转化的B细胞中受到动态调节，其mRNA和蛋白半衰期较短，且在凋亡过程中会迅速被加工处理。多种疗法可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。据报道，Mcl-1还介导CLL细胞对利妥昔单抗的耐药性。因此，我们研究了直接降低Mcl-1是否足以诱导细胞凋亡并增加对利妥昔单抗的敏感性。
我们在ALL细胞系和CLL患者的肿瘤细胞中使用Mcl-1特异性小干扰RNA来阻断Mcl-1的转录。
我们发现，单独下调Mcl-1足以促进ALL和CLL细胞的线粒体膜去极化和细胞凋亡。鉴于利妥昔单抗在B细胞恶性肿瘤中的重要性，接下来我们评估了下调Mcl-1对抗体介导杀伤作用的影响。通过小干扰RNA下调Mcl-1可增加对利妥昔单抗介导杀伤作用的敏感性，这一作用通过直接凋亡和补体依赖性细胞毒性实现，但并未增强抗体依赖性细胞毒性。
这些结果表明，Mcl-1是ALL和CLL的一个相关治疗靶点，下调Mcl-1有可能增强利妥昔单抗对表达CD20的淋巴细胞的治疗效果。
