Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation: induction of bax.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Szocinski JL,Khaled AR,Hixon J,Halverson D,Funakoshi S,Fanslow WC,Boyd A,Taub DD,Durum SK,Siegall CB,Longo DL,Murphy WJ

doi

10.1182/blood.v100.1.217

subject

Has Abstract

pub_date

2002-07-01 00:00:00

pages

217-23

issue

1

eissn

0006-4971

issn

1528-0020

journal_volume

100

pub_type

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