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Expert Opin Ther Targets. 2009 Dec;13(12):1459-72. doi: 10.1517/14728220903379565.

Targeting the BCL-2 family in malignancies of germinal centre origin.

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  • 1Growth Factor Signalling Laboratory, The Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK. l.spender@beatson.gla.ac.uk

Abstract

The germinal centre is a dynamic microenvironment where B-cell responses are honed. Antigen-specific cells undergo clonal expansion followed by antibody affinity maturation and class switching through somatic hypermutation and recombination of immunoglobulin genes respectively. The huge proliferative capacity of the B-cells and the potential for generating non-functional or autoreactive immunoglobulins, necessitate strict control measures. Pro-apoptotic signalling pathways via B-cell receptors, FAS and the TGF-beta receptor, ALK5, ensure that apoptosis of germinal centre B-cells is the norm and cells only survive to differentiate fully if they receive sufficient pro-survival signals to overcome their 'primed for death' status. Several of the B-cell signalling pathways converge on the intrinsic apoptotic machinery to control expression of the BCL-2 family of apoptosis regulators including BIM, the pro-survival factor BCL-X(L) and the BH3-only protein, BIK (recently identified as a mediator of a TGF-beta-induced default apoptosis pathway in human B-cells). It is a foreseeable hazard that cells undergoing genetic mutation and recombination events might unintentionally target some of these factors, resulting in defective programmed cell death. Here we discuss the function of BCL-2 family proteins in germinal centre reactions, their deregulation in malignancies of germinal centre origin, and the potential for targeting BCL-2-related proteins therapeutically in lymphomas.

PMID:
19922301
DOI:
10.1517/14728220903379565
[PubMed - indexed for MEDLINE]
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