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Regulation of apoptosis by CD40 in B-cell lymphoma

Regulation of apoptosis by CD40 in B-cell lymphoma
Regulation of apoptosis by CD40 in B-cell lymphoma

CD40 is a cell surface signalling molecule expressed on normal B-cells and B-cells malignancies.  Activations of CD40 (via binding CD40 ligand, CD40L) in normal B-cells promotes B-cell survival and is vital for activation of the immune response.  However, activation of CD40 can induce or prevent apoptosis in malignant B-cells.  Furthermore, CD40-activating agents are entering clinical trails as cancer therapies. 

B-cells were isolated from over twenty Non-Hodgkin’s lymphomas and non-malignant lymph nodes and the effect of CD40 ligation on apoptosis and expression of apoptosis regulators was assessed.  CD40L suppressed apoptosis in all B-cell malignancies tested, accompanied by significant increases in Bcl-XL protein expression and differential regulation of Bcl-X splicing and promoters.  Mcl-1 protein expression was also regulated by CD40 stimulation.  Although A20, survivin, Bfl-1 and BNIP3 (a novel CD40-target gene identified in this study) were regulated by CD40 in some samples, this was not consistent.  Antisense oligonucleotides to Bcl-XL and Mcl-1 demonstrated that these proteins were key for survival of lymphoma cells.  NF-κB mediated both the pro-survival effects of CD40 and upregulation of Bcl-XL and Mcl-1 expression.  Microarrays were developed and used to characterise CD40-induced gene expression.  This identified both novel CD40-target genes and also genes that were differentially regulated in cell lines with different survival outcomes to CD40 activation e.g. SLAM and SH2D1A.

Therefore, CD40 acts as a potent survival signal for primary B-cell lymphomas leading to regulation of the key anti-apoptotic proteins Bcl-XL and Mcl-1, via activation of NF-κB.  This raises concerns over forthcoming clinical trails utilising CD40 activation as a treatment for cancer but suggests that targeting Bcl-XL, Mcl-1 or NF-κB may be a useful approach for treating lymphoma.

University of Southampton
Dallman, Claire Louise
754bbb8b-1a6b-41ee-83a8-d47adadf3acf
Dallman, Claire Louise
754bbb8b-1a6b-41ee-83a8-d47adadf3acf

Dallman, Claire Louise (2003) Regulation of apoptosis by CD40 in B-cell lymphoma. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

CD40 is a cell surface signalling molecule expressed on normal B-cells and B-cells malignancies.  Activations of CD40 (via binding CD40 ligand, CD40L) in normal B-cells promotes B-cell survival and is vital for activation of the immune response.  However, activation of CD40 can induce or prevent apoptosis in malignant B-cells.  Furthermore, CD40-activating agents are entering clinical trails as cancer therapies. 

B-cells were isolated from over twenty Non-Hodgkin’s lymphomas and non-malignant lymph nodes and the effect of CD40 ligation on apoptosis and expression of apoptosis regulators was assessed.  CD40L suppressed apoptosis in all B-cell malignancies tested, accompanied by significant increases in Bcl-XL protein expression and differential regulation of Bcl-X splicing and promoters.  Mcl-1 protein expression was also regulated by CD40 stimulation.  Although A20, survivin, Bfl-1 and BNIP3 (a novel CD40-target gene identified in this study) were regulated by CD40 in some samples, this was not consistent.  Antisense oligonucleotides to Bcl-XL and Mcl-1 demonstrated that these proteins were key for survival of lymphoma cells.  NF-κB mediated both the pro-survival effects of CD40 and upregulation of Bcl-XL and Mcl-1 expression.  Microarrays were developed and used to characterise CD40-induced gene expression.  This identified both novel CD40-target genes and also genes that were differentially regulated in cell lines with different survival outcomes to CD40 activation e.g. SLAM and SH2D1A.

Therefore, CD40 acts as a potent survival signal for primary B-cell lymphomas leading to regulation of the key anti-apoptotic proteins Bcl-XL and Mcl-1, via activation of NF-κB.  This raises concerns over forthcoming clinical trails utilising CD40 activation as a treatment for cancer but suggests that targeting Bcl-XL, Mcl-1 or NF-κB may be a useful approach for treating lymphoma.

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Published date: 2003

Identifiers

Local EPrints ID: 465219
URI: http://eprints.soton.ac.uk/id/eprint/465219
PURE UUID: 8d7bb5e5-1e49-4827-b626-10d9643c4800

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Date deposited: 05 Jul 2022 00:29
Last modified: 23 Jul 2022 01:13

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Contributors

Author: Claire Louise Dallman

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