Mcl-1 is a relevant therapeutic target in acute and chronic lymphoid malignancies: down-regulation enhances rituximab-mediated apoptosis and complement-dependent cytotoxicity

Authors:
Hussain SR, Cheney CM, Johnson AJ, Lin TS, Grever MR, Caligiuri MA, Lucas DM, Byrd JC
In:
Source: Clin Cancer Res
Publication Date: (2007)
Issue: 13(7): 2144-50
Research Area:
Cancer Research/Cell Biology
Immunotherapy / Hematology
Cells used in publication:
697
Species: human
Tissue Origin: blood
RS4-11
Species: human
Tissue Origin: bone marrow
Raji
Species: human
Tissue Origin:
Platform:
Nucleofector™ I/II/2b
Abstract
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 antibody-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.