Modulation of malignant B cell activation and apoptosis by bcl-2 antisense ODN and immunostimulatory CpG ODN.
Inhibition of bcl-2 expression by antisense oligodeoxynucleotides (ODN) might render bcl-2 overexpressing malignant B cells more susceptible to chemotherapy. ODN containing unmethylated CG dinucleotides (CpG) are known to activate B cells. We studied the effects of two bcl-2 antisense ODN, with (G3139) or without CG dinucleotides (NOV 2009) within the sequence, and the effects of a nonantisense, CpG-containing ODN (ODN 2006) on activation and apoptosis of malignant B cell lines and primary B-CLL cells. Without cationic lipids, no antisense-mediated inhibition of bcl-2 synthesis was achieved with G3139 and NOV 2009. Instead, G3139, but not NOV 2009, induced similar changes as ODN 2006 in proliferation, expression of costimulatory and antigen-presenting molecules, as well as in bcl-2 and bcl-xL levels of primary B-CLL cells. G3139 and ODN 2006 inhibited in vitro, spontaneous apoptosis in B-CLL cells of patients with high serum thymidine kinase activity (s-TK, marker for proliferative activity of malignant B cells), whereas in patients with low s-TK activity, apoptosis was induced. In conclusion, our results suggest that modulation of malignant B cell apoptosis by G3139 depends on its immunostimulatory properties rather than on antisense-mediated reduction of bcl-2 expression. Immunostimulatory CpG ODN may have a therapeutic potential in patients with B-CLL, especially those with low s-TK activity.
Jahrsdörfer
B
B
Division of Clinical Pharmacology, Department of Internal Medicine, University of Munich, Ziemssenstrasse 1, 80336 Munich, Germany.
Jox
R
R
Mühlenhoff
L
L
Tschoep
K
K
Krug
A
A
Rothenfusser
S
S
Meinhardt
G
G
Emmerich
B
B
Endres
S
S
Hartmann
G
G
D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D005786:Gene Expression Regulation; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008213:Lymphocyte Activation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000494:pharmacology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D010714:Phosphatidylethanolamines; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics*; D013937:Thymidine Kinase / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D000276:Adjuvants, Immunologic; C494811:BCL2L1 protein, human; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; D020319:Oligodeoxyribonucleotides, Antisense; D010714:Phosphatidylethanolamines; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C020888:1,2-dielaidoylphosphatidylethanolamine; D013937:Thymidine Kinase