Abstract
BAFF, APRIL and their receptors regulate the survival, maturation and homeostasis of mature B-cells. Despite the lack of a functional role of BAFF/APRIL system during normal early B-cell development, previous studies indicated a contribution of these molecules in the pathogenesis of B-lineage acute lymphoblastic leukemia (B-ALL). Here, we evaluated the expression of this system in B-ALL and its involvement in spontaneous and drug-induced apoptosis of B-lymphoblasts, taking into consideration the distinct disease subtypes. We found that BAFFR is the most predominant aberrantly expressed receptor in B-ALL and that its expression, along with BCMA and APRIL, positively correlates with the maturation stage of B-lymphoblasts. Moreover, the binding of the E2A-PBX1 chimeric protein to the BAFFR promoter suggests that the transcriptional activator promotes the increase in BAFFR expression observed in about 50% of pre-B-ALL patients carrying the t(1, 19) translocation. BAFF binding to BAFFR led to the processing of NF-κB2 p100 in pre-B ALL cells suggesting that BAFFR can activate the NF-κB2 pathway in pre-B ALL cells. Surprisingly, we found that BAFF treatment promotes the cell death of primary BCR-ABL+ BAFFR+ pre-B-lymphoblasts in adult B-ALL. It also enhances glucocorticoid-induced apoptosis in the E2A-PBX1+ pre-B-ALL cell line 697. These data suggest that BAFF/BAFFR signaling in B-ALL cells differs from normal B cells and that it may affect the pathogenesis of the disease.
Highlights
B-cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, is an essential survival factor for Bcells
Analyzing the expression levels of BAFF receptor (BAFFR), TACI, B-cell maturation antigen (BCMA), BAFF, and APRIL relative to B2M transcripts, we found that BAFFR and BCMA transcripts are expressed by B-lineage acute lymphoblastic leukemia (B-ALL) cells (n = 63), at lower levels compared to primary B-cells or EBV lines, while TACI seems to be expressed only at background levels (Figure 1A)
BAFFR levels were higher in a proportion of patients carrying the E2A-PBX1 translocation compared to theE2A-PBX1-negative cohort (p = 0.014), with all of them suffering from pre-BALL (Figure 1F)
Summary
B-cell activating factor (BAFF), a member of the tumor necrosis factor (TNF) family, is an essential survival factor for Bcells. BAFF binds to three receptors differentially expressed by mature Bcell subsets [5]. BAFF receptor (BAFFR), which only binds BAFF, is expressed at high levels by all B-cell subsets from the stage of transitional B-cell except for germinal center Bcells and plasma cells. The transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) is expressed by marginal zone B-cells, switched memory B-cells and plasma cells, while the B-cell maturation antigen (BCMA) is expressed by plasma cells. Since BAFFR does not seem to be expressed before the stage of IgM+ immature B-cells [7, 8] and because inactivation of BAFF and BAFFR still allows normal development of Bcell precursors up to the stage of transitional B-cells [9, 10], BAFF and BAFFR are not required for the normal development of pro- and pre-B cells during these early stages of B-cell development
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