Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells.
Chronic lymphocytic leukemia (CLL) is an indolent malignancy of CD5+ B lymphocytes. CLL cells express CD40, a key regulator of B cell proliferation, differentiation, and survival. In nonmalignant B cells, CD40 ligation results in nuclear translocation and activation of NF-kappaB proteins. Based on observations that in some CLL cases, the tumor cells express both CD40 and its ligand, CD154 (CD40 ligand), we proposed a model for CLL pathogenesis due to CD40 ligation within the tumor. To evaluate this issue, we used freshly isolated CLL B cells to examine constitutive and inducible NF-kappaB activity by electrophoretic mobility shift assay. We consistently observed high levels of nuclear NF-kappaB-binding activity in unstimulated CLL B cells relative to that detected in nonmalignant human B cells. In each case examined, CD40 ligation further augmented NF-kappaB activity and prolonged CLL cell survival in vitro. The principle NF-kappaB proteins in stimulated CLL cells appear to be quite similar to those in nonmalignant human B cells and include p50, p65, and c-Rel. In a CD154-positive case, blocking CD154 engagement by mAb to CD154 resulted in inhibition of NF-kappaB activity in the CLL cells. The addition of anti-CD154 mAb resulted in accelerated CLL cell death to a similar degree as was observed in cells exposed to dexamethasone. These data indicate that CD40 engagement has a profound influence on NF-kappaB activity and survival in CLL B cells, and are consistent with a role for CD154-expressing T and B cells in CLL pathogenesis. The data support the development of novel therapies based on blocking the CD154-CD40 interaction in CLL.
Furman
R R
RR
Division of Hematology-Oncology, Department of Medicine, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021, USA.
Asgary
Z
Z
Mascarenhas
J O
JO
Liou
H C
HC
Schattner
E J
EJ
D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology*; D019013:CD40 Antigens / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand; D002470:Cell Survival / Q000276:immunology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology*; D008024:Ligands; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D023201:CD40 Ligand