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Mcl-1 Is a Relevant Therapeutic Target in Acute and Chronic Lymphoid Malignancies: Down-Regulation Enhances Rituximab-Mediated Apoptosis and Complement-Dependent Cytotoxicity

Authors' Affiliation: Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio

Requests for reprints: John C. Byrd, Division of Hematology-Oncology, Department of Internal Medicine, The Ohio State University, Room B302 Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: 614-293-9869; E-mail: john.byrd{at}osumc.edu.

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.

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