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Blood, 1 July 2002, Vol. 100, No. 1, pp. 217-223
NEOPLASIA
Activation-induced cell death of aggressive histology lymphomas
by CD40 stimulation: induction of bax
Jamie L. Szocinski,
Annette
R. Khaled,
Julie Hixon,
Douglas Halverson,
Satoshi Funakoshi,
William C. Fanslow,
Ann Boyd,
Dennis D. Taub,
Scott K. Durum,
Clay B. Siegall,
Dan L. Longo, and
William J. Murphy
From the Laboratory of Leukocyte Biology, Laboratory of
Molecular Immunoregulation, and SAIC-Frederick, National Cancer
Institute-Frederick Cancer Research and Development Center, Frederick,
Maryland; Laboratory of Immunology, National Institute on Aging,
Baltimore, Maryland; Immunex Corporation, Seattle, Washington; Biology
Department, Hood College, Frederick, Maryland; and Seattle Genetics,
Bothell, Washington.
CD40 is present on both normal and neoplastic B-lineage cells. CD40
stimulation of normal B cells has been shown to promote normal growth
and differentiation, whereas aggressive histology B lymphomas are
growth inhibited. The inhibition of neoplastic B-cell growth is
believed to occur via activation-induced cell death in which stimuli
that typically promote the growth of normal cells prevent the growth of
their neoplastic counterparts. We show here that CD40 stimulation using
either a soluble recombinant human CD40 ligand (srhCD40L) or anti-CD40
monoclonal antibody resulted in apoptosis of human Burkitt lymphoma
cell lines. Additional studies examining the mechanism of CD40-mediated
death revealed an increase in bax messenger RNA with a
subsequent increase in Bax protein in the mitochondria of the treated
cells. In vitro exposure of the cells to bax antisense
oligonucleotides resulted in a significant decline in Bax protein
levels and partial protection from CD40-mediated death, indicating that
induction of Bax was at least one mechanism underlying this inhibitory
effect of CD40 stimulation on lymphomas. When immunodeficient mice
bearing Burkitt lymphoma were treated with srhCD40L, significant
increases in survival were observed indicating a direct antitumor
effect as a result of CD40 stimulation in vivo. Overall, these results
demonstrate that CD40 ligation of aggressive histology B-lymphoma cells
results in inhibition both in vitro and in vivo and thus may be of
potential clinical use in their treatment.
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