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.

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Figures

Figure 1

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

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

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

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).

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