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.
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: David M Lucas; Patrick C Still; Lynette Bueno Pérez; Michael R Grever; A Douglas Kinghorn Journal: Curr Drug Targets Date: 2010-07 Impact factor: 3.465
Authors: Yuhong Du; Zaneta Nikolovska-Coleska; Min Qui; Lian Li; Iestyn Lewis; Raymond Dingledine; Jeanne A Stuckey; Krzysztof Krajewski; Peter P Roller; Shaomeng Wang; Haian Fu Journal: Assay Drug Dev Technol Date: 2011-03-11 Impact factor: 1.738
Authors: Gabriela Pavlasova; Marek Borsky; Vaclav Seda; Katerina Cerna; Jitka Osickova; Michael Doubek; Jiri Mayer; Raffaele Calogero; Martin Trbusek; Sarka Pospisilova; Matthew S Davids; Thomas J Kipps; Jennifer R Brown; Marek Mraz Journal: Blood Date: 2016-08-01 Impact factor: 22.113
Authors: Rong Chen; William G Wierda; Sherri Chubb; Rachael E Hawtin; Judith A Fox; Michael J Keating; Varsha Gandhi; William Plunkett Journal: Blood Date: 2009-02-20 Impact factor: 22.113