Modulation of NF-kappa B activity and apoptosis in chronic lymphocytic leukemia B cells. Academic Article uri icon

Overview

MeSH

  • Antibodies, Monoclonal
  • Antigens, CD40
  • CD40 Ligand
  • Cell Survival
  • Humans
  • Ligands
  • Membrane Glycoproteins
  • Tumor Cells, Cultured

MeSH Major

  • Apoptosis
  • B-Lymphocytes
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • NF-kappa B

abstract

  • 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.

publication date

  • February 15, 2000

has subject area

  • Antibodies, Monoclonal
  • Antigens, CD40
  • Apoptosis
  • B-Lymphocytes
  • CD40 Ligand
  • Cell Survival
  • Humans
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Ligands
  • Membrane Glycoproteins
  • NF-kappa B
  • Tumor Cells, Cultured

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed ID

  • 10657675

Additional Document Info

start page

  • 2200

end page

  • 2206

volume

  • 164

number

  • 4