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

Expert Opinion on Therapeutic Targets
Lindsay C Spender, Gareth J Inman

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...Continue Reading

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Citations

Jan 14, 2012·Molecular Cancer Research : MCR·Lindsay C Spender, Gareth J Inman
Nov 24, 2011·Advances in Hematology·Lindsay C Spender, Gareth J Inman
Jun 27, 2020·Zeitschrift Für Naturforschung. C, a Journal of Biosciences·Haiying FuMayu Huang

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