Anti-CD20- and B-cell receptor-mediated apoptosis: evidence for shared intracellular signaling pathways.
Clinical administration of the anti-CD20 antibody IDEC-C2B8 can induce remission of low-grade B-cell lymphoma. Whereas it has been suggested that the main mechanisms of action are complement-mediated and antibody-dependent cell-mediated cytotoxicity, we demonstrate that monoclonal antibody IDEC-C2B8 is a strong inducer of apoptosis in CD20-positive B-cell lymphoma cell lines reflecting different stages of lymphomagenesis. Thus, CD20-dependent apoptosis was inducible in human surface IgM-positive Burkitt's lymphoma cell lines as well as in more mature surface IgM-negative B-cell lymphoma cell lines carrying the t(14;18) translocation. Furthermore, in Burkitt's lymphoma cell lines, we observed a striking correlation between anti-CD20- and B-cell receptor-mediated apoptosis with regard to sensitivity toward the apoptotic stimuli and the execution of the apoptotic pathway. Thus, induction of anti-CD20- or B-cell receptor-mediated apoptosis involved rapid up-regulation of the proapoptotic protein Bax. In addition, we show similar changes in the mRNA expression level of two early response genes, c-myc and Berg36, as well as activation of the mitogen-activated protein kinase family members p44 (extracellular signal-regulated kinase 1) and p42 (extracellular signal-regulated kinase 2) and activation of activator protein 1 (AP-1) DNA binding activity. These data support our hypothesis that both pathways are mediated in part by the same signal-transducing molecules. These results might help explain the resistance and regression of lymphomas to IDEC-C2B8 and give new insights in the signaling cascade after CD20 ligation.
Mathas
S
S
University Medical Center Charité, Humboldt University, Robert-Rössle-Klinik, Department of Hematology, Oncology, and Tumor Immunology, Berlin, Germany.
Rickers
A
A
Bommert
K
K
Dörken
B
B
Mapara
M Y
MY
D018951:Antigens, CD20 / Q000378:metabolism*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism*; D015152:Blotting, Northern; D002051:Burkitt Lymphoma / Q000378:metabolism; D051817:Butyrate Response Factor 1; D020169:Caspases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D015151:Immunoblotting; D007075:Immunoglobulin M / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
D018951:Antigens, CD20; C494826:BAX protein, human; D051817:Butyrate Response Factor 1; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007075:Immunoglobulin M; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; C102034:ZFP36L1 protein, human; D051028:bcl-2-Associated X Protein; D012313:RNA; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020169:Caspases