Role of BAFF and APRIL in human B-cell chronic lymphocytic leukaemia - PubMed (original) (raw)
Review
Role of BAFF and APRIL in human B-cell chronic lymphocytic leukaemia
Stéphanie Haiat et al. Immunology. 2006 Jul.
Abstract
B-cell chronic lymphocytic leukaemia (B-CLL) is the most prevalent leukaemia in Western countries and is characterized by the gradual accumulation in patients of small mature B cells. Since the vast majority of tumoral cells are quiescent, the accumulation mostly results from deficient apoptosis rather than from acute proliferation. Although the phenomenon is relevant in vivo, B-CLL cells die rapidly in vitro as a consequence of apoptosis, suggesting a lack of essential growth factors in the culture medium. Indeed, the rate of B-CLL cell death in vitro is modulated by different cytokines, some favouring the apoptotic process, others counteracting it. Two related members of the tumour necrosis factor family, BAFF (B-cell activating factor of the TNF family) and APRIL (a proliferation-inducing ligand), already known for their crucial role in normal B-cell survival, differentiation and apoptosis, were recently shown to be expressed by B-CLL cells. These molecules are able to protect the leukaemic cells against spontaneous and drug-induced apoptosis via autocrine and/or paracrine pathways. This review will focus on the role of BAFF and APRIL in the survival of tumoral cells. It will discuss the expression of these molecules by B-CLL cells, their regulation, transduction pathways and their effects on leukaemic cells. The design of reagents able to counteract the effects of these molecules seems to be a new promising therapeutic approach for B-CLL and is already currently developed in the treatment of autoimmune diseases.
Figures
Figure 1
Schematic representation of BAFF and APRIL signalling pathways. See text for the significance of the various components of these transduction pathways.
Figure 2
Membrane expression of the three BAFF receptors on B-CLL cells. The expression of the three BAFF receptors was analysed on purified leukaemic B cells from 18 B-CLL patients by membrane immunofluorescence and flow cytometry with specific fluorescence-labelled antibodies against BAFF-R, TACI and BCMA and their corresponding fluorescence-labelled isotypes. Results are expressed as the percentages of positive cells (%) and their mean fluorescence intensity (MFI), as estimated according to Kolmogorov—Smirnov.
Figure 3
Activation by BAFF of the non-canonical NF-κB pathway in B-CLL cells. Leukaemic cells from B-CLL patients were incubated for 18 hr in the presence or in the absence of BAFF 0·25 μ
m
. Total lysates were analysed for the presence of activated NF-κB using a Transam ELISA kit (Active Motif). The active form of NF-κB is detected by its binding to a κB oligonucleotidic consensus sequence immobilized in the wells of an ELISA microplate. The non-canonical pathway is evidenced using either an anti-p52 or anti-RelB antibody that recognizes conformation epitopes of the corresponding proteins bound to κB. A second anti-immunoglobulin antibody conjugated with peroxidase, followed by addition of the peroxidase substrate allows a colorimetric detection at 450 nm of the complexes, using a Victor® 2 microplate spectrophotometer.
Figure 4
Transfection of B-CLL cells with BAFF siRNA stimulates spontaneous apoptosis. Leukaemic cells from a B-CLL patient were transfected by nucleofection (Amaxa) with a scramble siRNA (Control) or with one or two BAFF-specific siRNA (si RNA1 and si RNA2). After overnight incubation, apoptosis induction was estimated by measuring the percentage of annexinV-FITC-labelled cells (a) and the enrichment in cytoplasmic nucleosomes, in comparison with control cells taken as 100% (b).
References
- Keating MJ. Chronic lymphocytic leukemia. Semin Oncol. 1999;26:107–14. - PubMed
- Kay NE, Hamblin TJ, Jelinek DF, Dewald GW, Byrd JC, Farag S, Lucas M, Lin T. Chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program) 2002:193–213. - PubMed
- Byrd JC, Stilgenbauer S, Flinn IW. Chronic lymphocytic leukemia. Hematology (Am Soc Hematol Educ Program) 2004:163–83. - PubMed
- Decker T, Hipp S, Ringshausen I, Bogner C, Oelsner M, Schneller F, Peschel C. Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood. 2003;101:278–85. - PubMed
- Caligaris-Cappio F. Biology of chronic lymphocytic leukemia. Rev Clin Exp Hematol. 2000;4:5–21. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Miscellaneous