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

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.

• Authors: Syed-Rehan A Hussain, Carolyn M Cheney, Amy J Johnson, Thomas S Lin, Michael R Grever, Michael A Caligiuri, David M Lucas, John C Byrd
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 13 Issue 7 Pg. 2144-50 (Apr 01 2007) ISSN: 1078-0432 [Print] United States
• PMID: 17404098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins
• Proto-Oncogene Proteins c-bcl-2
• RNA, Small Interfering
• Rituximab
• Complement System Proteins

Topics

• Antibodies, Monoclonal (pharmacology)
• Antibodies, Monoclonal, Murine-Derived
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Blotting, Western
• Cell Line, Tumor
• Complement System Proteins
• Cytotoxicity, Immunologic (drug effects)
• Down-Regulation
• Flow Cytometry
• Humans
• Leukemia, Lymphoid (metabolism)
• Membrane Potentials (drug effects)
• Mitochondrial Membranes (metabolism, pathology)
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasm Proteins (drug effects, metabolism)
• Polymerase Chain Reaction
• Proto-Oncogene Proteins c-bcl-2 (drug effects, metabolism)
• RNA, Small Interfering
• Rituximab
• Transfection