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Role of BAFF/BAFF-R axis in B-cell non-Hodgkin lymphoma

Critical Reviews in Oncology/Hematology

Abstract

B-cell activating factor (BAFF), as a member of the tumor necrosis factor (TNF) ligand family, plays important roles in B-cell homeostasis, tolerance, and malignancy. BAFF binds to three receptors of TNF, TACI, BCMA and BAFF-receptor (BAFF-R). In particular, the BAFF/BAFF-R pathway is crucial to the survival and growth of mature normal and malignant B-cells. BAFF is displayed on the cell surface or is released in a soluble form after cleavage from the plasma membrane. BAFF-R as the main BAFF receptor is expressed mainly on B-cells. Aberrant BAFF expression was found in malignant B-cells from B-cell non-Hodgkin lymphoma (B-NHL) patients, which protects these cells from spontaneous or drug-induced apoptosis and stimulated NF-κB activation via autocrine and/or paracrine pathways. However, the mechanisms involved in the gene expression and regulation of BAFF or BAFF-R has not been elucidated. More importantly, the design of reagents able to counteract BAFF/BAFF-R pathways may be of therapeutic value for B-NHL. Results of ongoing clinical trials with BAFF or BAFF-R antagonists are eagerly awaited.

Keywords: B-cell activating factor, B-cell activating factor receptor, B-cell non-Hodgkin lymphoma.

1. Introduction

B-cell activating factor (BAFF) was also known as B lymphocyte stimulator (BLyS) protein, TNF and apoptosis ligand-related leukocyte-expressed ligand-1 (TALL-1), zTNF4, CD257, TNFSF13B, TNFS20 (TNF superfamily member) and THANK (TNF homolog that activates apoptosis, NF-κB and c-Jun NH2-terminal kinase) [1] . It is a member of the TNF superfamily (TNFSF), which also involves another two members: the TNF-like weak inducer of apoptosis (TWEAK) and a proliferation-inducing ligand (APRIL) [1] . BAFF was firstly identified from a human neutrophil/monocyte-derived complementary DNA library in the late 1990s [2] and [3], produced by monocytes, macrophages, neutrophils, dendritic cells, activated T-cells, follicular dendritic cells, splenic radiation-resistant stromal cells, astrocytes, fibroblast-like synoviocytes, nurse-like cells, osteoclasts and ductal epithelial cells [4] . As the key regulator in normal B-cells proliferation, activation and differentiation, BAFF exerting its effect by binding to three known receptors: transmembrane activator and calcium modulator cyclophilin ligand interactor (TACI), B-cell maturation antigen (BCMA) and BAFF-R [also known as BAFF receptor 3 (BR3), CD268 or TNFRSF17]. BAFF-R and BCMA expressions are restricted to B-cells, whereas TACI is found on both B-cells and activated T-cells [5] and [6]. Among the three receptors, BAFF-R is specific for BAFF, whereas TACI and BCMA also bind to APRIL [7] . BAFF binding to various B-cell lines correlated strongly with the surface expression of BAFF-R, less so with TACI, and not at all with BCMA expression [5] .

In animal models, transgenic mice overexpressing BAFF have a dramatic increase in mature B-cells, enlarged spleens, high plasma cell numbers, and high levels of autoantibodies. Besides, peripheral blood mature B-cells from mice overexpressing BAFF have an increase of in Bcl-2 protein expression [8] , while BAFF-deficient mice reveal an almost complete loss of follicular and marginal zone B-cells [9] . Furthermore, an A/WySnJ mouse in which BAFF-R locus is disrupted displays a B-cell phenotype qualitatively similar to that of the BAFF-deficient mice [5] . In contrast, BCMA-deficient mice have no B-cell deficiency [10] , and TACI-deficient mice have increased numbers of peripheral B-cells coupled with reduced responses to carbohydrate (T cell-independent) antigens [11] and [12]. In humans, increased concentrations of soluble BAFF are observed in different pathological conditions, which may be as diverse as autoimmune diseases, B-cell malignancies, and primary antibody deficiencies (PAD) and a positive effect of BAFF on pathological autoimmune and malignant cells have been demonstrated in vitro [13] . The findings that BAFF and BAFF-R were expressed aberrantly in human leukemia and lymphoma cells lead to the hypothesis that BAFF/BAFF-R axis may be involved in the development and pathogenesis of these diseases and also provides an additional survival mechanism to the expressing cells. The implications of dysregulation of a receptor capable of imparting survival and costimulatory signals are vast. Until now, the underlying mechanism responsible for BAFF/BAFF-R signaling cascade is poorly understood. In this review, we primarily focused on a current understanding of the distinctive biology, signal transduction and impact of BAFF/BAFF-R axis, and discuss the clinic relevance and therapeutic value as a target in B-cell non-Hodgkin lymphoma (B-NHL).

2. Characterization of BAFF

BAFF is a type II membrane-bound protein that can released as a soluble form after cleavage at a consensus furin cleavage site [14] . The soluble BAFF can be increased following stimulation with CD40L, IL-10, G-CSF, IFN-α and IFN-γ [15] or infection with the human herpes virus, Epstein Barr virus (EBV) [16] . However, in fact, BAFF offers a bunch of variants: membrane-bound or soluble, monomer or trimers, homotrimers or heterotrimers, heterotrimers with APRIL or heterotrimers with TWEAK [1] . At neutral or basic pH, 20 trimers of soluble recombinant human BAFF associate into a 60-mer virus-like structure, which irreversibly dissociates into trimers at acidic pH [17] . This 60-mer virus-like structure is a biologically active entity that can bind receptors and is moderately more active than trimers in the in vitro assays [18] . Oligomerization of BAFF 3-mer into 60-mer in human BAFF can be prevented by mutation of His218, a residue critical for 3-mer-to-3-mer interactions, but not for receptor binding [17] .

In the human BAFF gene, exon 1 codes for the transmembrane domain and flanking regions, exon 2 for the furin processing site, and exons 3–6 for the TNF homology domain (THD), which binds to receptors [19] . The crystal structure of the THD of BAFF has been determined at 2.8 Å resolution and presents significant differences with other TNF family members, including an unusually long D–E loop that participates in the formation of a deep, concave and negatively charged region in the putative receptor binding site [20] . This characterization in the D–E loop structure and electrostatic surface potentials of BAFF may be important for determining binding specificities for BCMA, TACI and BAFF-R.

Soluble BAFF predominantly functions both in vitro and in vivo. It may induce human B-cell proliferation; contribute to immunoglobulin (Ig) isotype switching by inducing B-cells to secrete IL-10 [21] ; stimulate Ig production in vitro when the B-cell receptor (BCR) was crossed linked with anti-IgM [22] , also up-regulate a B-cell specific transcription factor Pax5/B-cell specific activator protein (Pax5/BSAP) activity and its target CD19 [23] . It is reported that BAFF also increased the chemotactic response of primary human B-cells to CCL21, CXCL12, and CXCL13 through a dose dependent mode, reaching a maximum value at 25 ng/mL. At this BAFF dosage, it increased B-cell chemotaxis by 1.6-fold (CXCL12, CCL21) or 2.4-fold (CXCL13) after 16 h of incubation but not correlate with the increase in CXCR4, CXCR5, or CCR7 expression or with the impairment of chemokine-induced receptor internalization. Furthermore, BAFF-induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was highly dependent on the activation of PI3K/AKT, NF-κB, and p38MAPK pathways. This phenomenon, however, was not observed in APRIL [24] . BAFF augment the responses of not only B-cells, but also T-cells. It is able to enhance the in vitro response of CD4+ andCD8+ T-cells, as well as naive and effector T-cells [25] . BAFF preferentially drives the expansion of Th1 and Th17 pathways and augments Th1-associated inflammatory responses [26] .

Despite the well-known predominant effect of soluble BAFF in vivo, the function of membrane-bound BAFF remains unclear. The potential effects of membrane-bound BAFF may include (I) the production or survival of peritoneal B-cells, (II) the production of basal levels of IgA, (III) the differentiation of B-cells and/or (IV) the up-regulation of CD23 expression [27] . Besides, a splice isoform of BAFF (ΔBAFF) was identified opposing the effects of full length BAFF. Mice transgenic for ΔBAFF have reduced B-cell numbers and T-cell-dependent antibody responses [28] . Unlike full length BAFF, ΔBAFF lacks 57 nucleotides encoding the A-A1 loop, thus is not shed readily from cells as well as failing to bind to BR3, suggesting that ΔBAFF inhibits BAFF-dependent signaling by causing intracellular retention of full length BAFF and forming mixed heterotrimers which fail to bind to BAFF receptors [29] .

3. Characterization of BAFF-R

BAFF-R is a type III transmembrane protein containing only four cysteine residues in its extracellular/ligand binding domain, making it the smallest cysteine-rich domain (CRD) in the TNF receptor family [30] and [31]. The human BAFF-R gene (TNFRSF13C) was localized to chromosome 22q13.1–13.31. Specific function of BAFF-R is mediated by a sequence motif “PVPAT” within the cytoplasmic domain of BAFF-R [32] . In addition to its integral presence in the plasma membrane, BAFF-R is also found elsewhere in other cellular fractions, including cytoplasm, nuclear envelope and nucleoplasm [33] . In mice, BAFF-R is expressed on transitional and mature B-cells, and in humans, BAFF-R is widely expressed by all B-cells, except for bone marrow plasma cells [7] . Although BAFF-R is expressed on the majority of B-cells, its expression is not restricted to the B-lineage. A small subset of resting human and murine T-cells have been found to bind soluble BAFF through BAFF-R, and the expression of BAFF-R increases following in vitro stimulation [34] . Hence, T-cell responses, such as typical delayed-type hypersensitivity reactions, are also influenced by BAFF/BAFF-R interaction [35] .

As other TNF receptors, BAFF-R signaling is dependent on TNF receptor associated factors (TRAF). TRAF binding site in BAFF-R's cytoplasmic tail is unique in that it exclusively associates with TRAF3, an adaptor molecule that function as a trimer in solution [36] . BAFF/BR3 signaling through TRAF3 induces the processing of p100 to p52 by the non-canonical NF-κB pathway [37] , which was negatively regulated by TRAF2 [38] . In addition, mutation of the TRAF3 binding site on BR3 blocks p100 processing. It seems that TRAF3 acted as a positive regulator of BAFF/BR3 signaling pathway. However, TRAF3 was important for adaptor molecule NF-κB activator (Act1) dependent negative regulatory events [39] .

4. Mechanisms of BAFF/BAFF-R-mediated survival of B-cells

BAFF/BAFF-R signaling enhances B-cell survival, growth and metabolic fitness, but does not impact central B-cell selection in the BM because immature B-cells have extremely low expression of BAFF-R. After the naïve B-cells exit from the BM, B-cells encounter self-antigens, experience transitional stage and then compete for survival signals mediated cooperately by BCR and BAFF-R [40] . The complicated nature of BCR signaling, which programs the cells for deletion/anergy at the early transitional stage and then promotes survival at the late transitional stage, is coincident with the crucial survival signal initiated by the ligation of BAFF-R. Firstly, BCR crosslinking in naïve cells triggers the expression of BAFF-R through the PI3K signaling pathway [41] . In addition, BCR's constitutive baseline signal induction is responsible for generating p100, which serves as a substrate for the alternative NF-κB pathway essential for BAFF-R-mediated survival [42] . Secondly, BAFF-R engagement up-regulates CD19 expression by modulating the transcription factor Pax5, thus enhancing BCR signaling [7] . Finally, BCR and BAFF-R inhibit additively apoptotic pathways by altering the expression of different pro-survival and pro-apoptotic proteins [43] .

NF-κB pathway is evidenced as a common downstream of the three known BAFF receptors in normal B-cells. Mice that lack components of the non-classical NF-κB pathway develop phenotypes similar to those of BAFF or BAFF-R-deficient mice [44] . NF-κB/Rel family of transcription factors consist of five members, that is, RelA (p65), c-Rel, RelB, NF-κB1 (p50 and its precursor p105), and NF-κB2 (p52 and its precursor p100), which can form homo- and heterodimers and are kept inactive by cytoplasmic association with inhibitory proteins. Physiologic activation of NF-κB occurs mainly through either the canonical or the alternative pathway [45] . It is known that BAFF-R is able to induce NF-κB activation through both pathways ( Fig. 1 ). Upon BAFF binding, BAFF-R induces the processing of p100 to p52 by the non-canonical NF-κB pathway in a NF-κB inducing kinase (NIK) and IκB kinase (IKK) dependent manner, thereby producing the bulk of p52 found in resting B-cells. Then p52 dimerizes with RelB to form the p52/RelB active heterodimer that translocate to the nucleus and regulates gene expression [46] . Additionally, BAFF-R can activate NF-κB in the canonical pathway manner by activating the IKK complex consisting of IKKα (IKK1), IKKβ (IKK2) and IKKγ (also known as NEMO for NF-κB essential modifier). Activated IKK complex induces the phosphorylation and subsequent degradation of IκB. Then the nuclear translocation of p50-containing NF-κB heterodimer is released to translocate into the nucleus, activating gene transcription [47] . In addition to activating NF-κB pathways in the plasma membrane, BAFF-R also promotes normal B-cells and B-NHL-cells survival and proliferation by bounding to NF-κB targeted promoters including BAFF, CD154, Bcl-xL, IL-8, and Bfl-1/A1, promoting the transcription of these genes [33] . Despite progress in this area of research, the mechanisms by which BAFF/BAFF-R mediates the activation of NF-κB in both the canonical and noncanonical pathways are not fully understood.

gr1

Fig. 1 Schematic summary of BAFF/BAFF-R signaling pathways in B cells. BAFF plays a crucial role in B-cell proliferation, survival and apoptosis. BAFF binds to three receptors of TNF, TACI, BCMA and BAFF-R. Among the three receptors, BAFF-R is specific for BAFF, whereas TACI and BCMA also bind APRIL. NF-κB pathway is evidenced a common downstream of BAFF receptors in B-cells. BAFF/BR3 is able to induce NF-κB activation through both pathways (canonical pathway and alternative pathway), then regulate transcription of the target genes and protect B cells against spontaneous and drug-induced apoptosis.

Although NF-κB is important for BAFF/BAFF-R signaling pathway, Mecklenbräuker et al. [48] suggested another previously unknown BAFF-induced and erine/threonine protein kinase C δ (PKCδ)-mediated nuclear signaling pathway that regulates B-cell survival. The results showed that treatment of B-cells with the potent B-cell survival factor BAFF prevents nuclear accumulation of PKCδ. This found revealed that BAFF promotes B-cell survival not only through the NF-κB-mediated signaling pathway, but also by actively preventing nuclear translocation of PKCδ. Recent models suggest that BAFF-dependent signaling through BAFF-R results in a coordinated assembly of a regulatory complex consisting of cIAP1, cIAP2, TRAF2, TRAF3 and NIK. Formation of these complex results in ubiquitin-mediated proteasome degradation of TRAF3 followed by NIK stabilization and NF-κB2 activation, and direct recruitment of TRAF2 to another tumor necrosis factor receptor (TNFR) superfamily member CD40 is an essential step in CD40-induced cIAP-mediated TRAF3 degradation [49] and [50]. In addition to NF-κB2 activation, BAFF-R has been shown to be essential for BAFF-mediated phosphorylation of AKT and Erk1/2 through IKK1 [51] . A newly identified member of the BAFF-R-proximal signaling complex was TRAF6. Though not required for association of TRAF2 and TRAF3 with BAFF-R, TRAF6 is recruited to BAFF-R, with important roles in BAFF-R-induced IκBα activation and BAFF-R-mediated rescue from Fas-induced apoptosis [52] .

5. BAFF/BAFF-R axis in lymphomas

5.1. BAFF, a key player in tumor microenvironment

The FACS analysis showed that splenic B-cells cultured with BAFF increased in size, otherwise lost cell volume. Consistent with this supposition, glucose metabolism, amino acid uptake and basal RNA metabolism were all increased when B-cells are stimulated with BAFF [53] . In NHL, aberrant production of BAFF by malignant B-cells themselves (i.e. autocrine) or by supporting cells present within the microenvironmental niche occupied by the malignant B-cells (i.e. paracrine) may facilitate their growth and survival [34] .

The B-cell tumors tested, expressed none or very low levels of membrane-bound BAFF protein. Yet, serum BAFF levels were significantly elevated in patients with most NHL compared to those in healthy donors, and high BAFF levels correlated with aggressive disease and a poor response to therapy [54] . One report got the result from 66 diffuse large B-cell lymphoma (DLBCL) patients that serum BAFF predicted prognosis better than APRIL in treated with rituximab plus CHOP chemotherapy. High BAFF group had less numbers of complete responders to rituximab-CHOP, and more relapses or progression after or during treatment. Furthermore, multivariate analysis showed that serum BAFF was an independent prognostic factor for overall survival (OS) and progression-free survival (PFS) [55] . A current study found that among 51 hematological malignancies patients after allogeneic hematopoietic stem cell (allo-HSCT) transplantation, the ones with chronic graft-versus-host disease (cGVHD) have elevated BAFF to B-cell ratios with significantly increased activation of AKT, ERK and decreased expression of proapoptotic BH3-only protein Bim compared to the ones without cGVHD [56] . Additionally, BAFF has been reported to up-regulate anti-apoptotic Bcl-2 family members including: Bcl-2, Bcl-xL or Bfl-1/A1, or alternatively inhibit the induction of the pro-apoptotic proteins Bak or Bim [53] . In some NHLs, exogenous BAFF up-regulated c-Myc, an inducer of cell proliferation; down-regulated p53, an inhibitor of cell proliferation; and increased Bcl-6, an inhibitor of B-cell differentiation [57] .

Interestingly, it is reported that serum BAFF levels increased after four weekly doses of rituximab as initial therapy in patients with grade I follicular lymphoma (FL). Patients with higher BAFF levels post-rituximab were more likely to have had a complete response to treatment [58] . Similar phenomenon was observed in patients with autoimmune diseases treated with rituximab [59] . The possible explanation may be ascribed to a compensatory mechanism for the dramatic depletion of B-cells and the available BAFF receptors by rituximab. In other hand, we could not disregard the veiled mechanism that the binding of rituximab to malignant B-cells activated BAFF-producing immune cells resulting in elevated BAFF levels.

As an essential component of the lymphoma microenvironment, BAFF has long been recognized as a ‘sanctuary site’ for lymphoma cells during traditional chemotherapy. Nishio et al. [60] has confirmed that nurse like cells are able to express BAFF, which can promote survival of chronic lymphocytic leukemia (CLL) cells via a paracrine pathway. Four years later, Lwin et al. [61] showed that bone marrow stromal cells (BMSC) protected B lymphoma cells from apoptosis through stromal niches with high BAFF concentration. In his study, abundant BAFF was detected in the BMSC cell line and primary BMSCs by flow cytometry, RT-PCR and immunoblotting. BAFF levels were much higher in BMSCs than in lymphoma cells, and lymphoma cells adhesion to BMSCs augmented BAFF secretion two-fold through up-regulation of BAFF gene expression. Addition of BAFF counteracted drug-induced apoptosis and elicited a reduction in spontaneous apoptosis in primary lymphomas. In contrast, neutralization of BAFF significantly enhanced lymphoma cell response to chemotherapy and overcame stroma-mediated drug resistance. Medina et al. [62] even observed that co-cultured with primary BMSCs through BAFF secretion and NF-κB activation pathways, mantle cell lymphoma (MCL) cells can be maintained ex vivo for at least 7 months and that the MCL cells retain their original phenotype and continue to require MCL-hMSC interactions for proliferation and survival.

5.2. New insights into BAFF-R expression and signaling

Given that BAFF-R is the most unique of the 3TNFRs for BAFF, many studies have focused on the distribution of BAFF-R expression among distinct subsets of human lymphoid cells and their neoplastic counterparts. Most circulating human B-cells and a small subset of T-cells are BAFF-R-positive [63] . Rodig et al. [64] studied on 116 cases of B-cell lymphoproliferative disorders, finding that 77 (78%) specimens were BAFF-R-positive by immunohistochemical and/or flow cytometric immunophenotypic analysis, including most cases of MCL, FL, marginal zone lymphoma (MZL), CLL, hairy cell leukemia (HCL), and DLBCL. In contrast, cases of precursor B lymphoblastic lymphoma, Burkitt lymphoma, and Hodgkin lymphoma (HL), T-cell lymphomas exhibited weak or negative staining for BAFF-R. By use of lymph node or spleen specimens, the mean fluorescence intensity value of BAFF-R detected in B-cells from normal individuals and from patients with DLBCL, MCL and MZL was comparable, whereas those from FL and CLL displayed somewhat lower BAFF-R expression (p < 0.0001 for both) [65] .

Just as the point at which BAFF-R firstly appears on the surface of human B-cells provides essential clues to its transcriptional control, so too does the point at which B-cells no longer express BAFF-R. However, there have been no reports on this point. We only get the information from previous studies that BAFF-R expressed on most mature tumor B-cells and not at the immature stage or final differentiated stage of B-cell lymphoma [66] . It is noteworthy that Tussiwand et al. [67] reported that the expression of BAFF-R is at first detectable on a fraction of mouse CD191+CD931+IgM1+CD23 and human CD191+CD101+IgM1+ BM B-cells. He also indicated that BAFF-R expression is tightly regulated by BCR signaling during B-cell development, namely a down-modulation on immature B-cells and up-regulation on mature B-cells. The expression is correlated with positive selection. Apart from this, Mihalcik et al. [68] showed the expression of BAFF-R on the surface of precursor B-acute lymphoblastic leukemia (ALL)-derived precursor B-cell lines and revealed that these cells acquire BAFF-R expression through premature transcriptional activation of the BAFF-R promoter in coordination with regulatory transcription factor c-Rel. Indeed, c-Rel is bound to TNFRSF13C promoter site, a coordinator of transcriptional control at the heart of the B-cell survival axis from the final stages of ontogeny until the B-cell loses BAFF-R expression upon terminally differentiating into an Ab-secreting plasma cell. c-Rel small interfering RNA transfections in BAFF-R-expressing lines demonstrated a coincident knockdown of both c-Rel and BAFF-R mRNA [69] . These findings are interesting because BAFF-R and c-Rel are dysregulated in other types of aggressive B-NHL [70] . At the same year, Parameswaran et al. [71] got the same conclusions: adopting both Western blots and FACS analysis to detect BAFF-R, expression of the BAFF-R detected on both Ph-positive and Ph-negative ALL samples, including original ALL bone marrow and blood samples, was BAFF-R positive.

Recent publications highlight the role of gene mutations in the pathogenesis of NHL. Increasing genetic evidence suggest an association between the development of human disease with genetic variation in genes encoding BAFF and its receptors. Single nucleotide polymorphisms (SNP) in TNFSF13B (BAFF gene) were associated with elevated BAFF levels and NHL-developing risk [72] . Hildebrand [52] and colleagues identified a novel mutation in TNFRSF13C (BAFF-R gene), that is present in both tumor and germline tissue from a subset of NHL patients with the highest incidence in FL (10%). This mutation encodes a His159Tyr substitution in the cytoplasmic tail of BAFF-R adjacent to the TRAF3 binding motif. Signaling through this mutant BAFF-R generates increased NF-κB1 and NF-κB2 activity and increased immunoglobulin production compared with the wild-type (WT) BAFF-R.

6. BAFF/BAFF-R axis in CLL

Novak et al. [73] firstly demonstrated BAFF mRNA-expressed CLL cells were found to express low levels of cell surface BAFF, whereas the ones negative by RT-PCR, were also found to be negative for BAFF protein by FACS. Although the presence of BAFF mRNAs and proteins were evidenced in purified normal and CLL cells, only CLL cells displayed membranous expression, suggesting the existence of a different transport mechanism [74] . Another study compared the expression of BAFF in 183 CLL patients and 20 normal donors. It was found that decreased soluble BAFF levels in the plasma of CLL patients compared to healthy controls by ELISA, high BAFF mRNAs levels were in CD19+ cells from CLL patients than in normal CD19+ lymphocytes by RT-PCR, and greater intracellular BAFF expression in CLL patients than in normal controls by flow cytometry analysis [75] . When detected by ELISA, many studies have shown a drop in circulating BAFF levels in CLL patients in comparison with healthy subjects. Elevated BAFF levels only in patients with familial CLL raises the possibility of a causative link [76] . Interestingly, Kern et al. [74] , using a sensitive technique-SELDI-TOF, detected higher levels of serum soluble BAFF in CLL patients than in normal control. The presence of soluble BAFF-containing complexes in the serum of CLL patients might explain the differences in soluble BAFF detection between ELISA and SELDI-TOF techniques. Although the serum level of BAFF was lower in CLL patients than in healthy controls by ELISA, it might be a useful prognostic variable for clinical outcome in CLL. It was reported that BAFF correlated significantly with some clinical prognostic parameters, such as a correlation between the level of soluble BAFF and immunoglobulin heavy chain variable (IGHV) mutational status [77] , a relationship between intracellular BAFF and CD38/ZAP-70 expression [75] . One study showed that BAFF serum level predicts time to first treatment in early CLL [78] . In CLL patients, large tumor mass might be the main source of BAFF even if cells had low secretory capacity, but until now no method is able to indicate whether leukemic B-cells with BAFF expression could secrete the proteins.

Haiat et al. [77] firstly investigated the expression of the three known BAFF receptors by membrane immunofluorescence in 18 CLL patients, finding that BAFF-R was the main receptor detected on the CLL cells whereas BCMA and TACI, although present, were detected at a much lower level. Besides, Endo et al. [79] examined for surface expression of BCMA, TACI, and BR3 on CLL cells using flow cytometry, finding BAFF-R on all 11 samples with the highest average mean fluorescence intensity ratio (MFIR). Furthermore, data reported by Lin et al. [80] showing a trend of low BAFF-R expression in CLL cells. Recently, one study showed that the CLL cells had fewer surface-bound BAFF with less BAFF-binding capacity than their normal counterparts did. However, levels of BAFF-R mRNA were normal to elevate while intracellular BAFF-R protein levels were indeed decreased in the CLL cells relative to normal mature B-cells [68] . On the above results, the post-transcriptional dysregulatory mechanisms were proposed, suggesting that down-regulation was an abnormality intrinsic to the malignant clone but remains to be elucidated for why indolent lymphomas just like CLL cells down-regulate BAFF-R.

CLL cells can be rescued from apoptosis through BAFF/BAFF-R signaling pathway. Adding soluble BAFF protected CLL cells against spontaneous and drug-induced apoptosis and also stimulated NF-κB activation. Conversely, adding soluble anti-BAFF antibodies or inhibition of BAFF expression by transfecting BAFF-specific siRNAs was accompanied by a stimulation of apoptosis [74] and [77]. The level of NF-κB activation may be high in CLL cells compared with that of normal B-cells [81] . Sustained activation of NF-κB may be critical for the survival of CLL cells. Signaling through BAFF/BAFF-R axis activates the canonical and alternative NF-κB pathways [37] . However, Endo et al. [79] demonstrated that signaling through BAFF-R only activated the alternative NF-κB pathway in CLL cells and blocking BAFF-R did not inhibit the capacity of BAFF to support CLL cell survival in vitro. So the mechanisms by which BAFF/BAFF-R mediates the activation of NF-κB in the canonical or noncanonical or both pathways are remain to be elucidated.

7. BAFF/BAFF-R-targeting therapy

BAFF can be expressed by the neoplastic B-lymphoid cells themself or by neighboring cells in the tumor microenvironment [82] . Serum level of BAFF may indicate disease mechanisms and the degree of activity. Thus, the blockade of BAFF and their receptors can be a plausible therapeutic strategy in B-cell malignancies. Anti-BAFF or anti-BAFF-R monoclonal Abs is currently being evaluated in systemic lupus erythematosus (SLE) ( Table 1 ). In patients with SLE, belimumab (fully human IgG1 monoclonal antibody against BAFF), as the first new drug in recent 50 years to be approved for the treatment of SLE, reduced total peripheral B-cell numbers and immunoglobulin levels and improved disease activity by a reduction in the frequency of lupus flares [83] . Two other new BAFF-R antagonists, Briobacept (BAFF receptor fusion protein) and A-623 (peptide fusion protein), have been developed currently in clinical trials [84] . In addition, antibodies were also engineered to induce cell incorporating the features of both anti-CD20 antibodies and BAFF-R-Fc proteins in one compound. Mice treated with such antibodies exhibited significantly larger B-cell drop in certain subsets and qualitatively distinct outcomes that compared to either BAFF-R-Fc or anti-CD20 alone treated mice [85] . Lyu and his colleagues [86] recently generated a fusion protein Bax345/BAFF containing the truncated form of proapoptotic protein Bax (Bax345) at the N-terminus followed by a 218 linker to the BAFF. Specific delivery of Bax345/BAFF to malignant B-cells expressing the BAFF receptors drove cells into apoptosis by mitochondrial dysfunction and treatment of cells with Bax345/BAFF induced down-regulation of Mcl-1, X-IAP, and survivin. Similarly, a new generated fusion toxin rGel/BAFF showed therapeutic effect in mice models of mantle cell lymphoma. rGel/BAFF fusion toxin prolonged both median survival and OS especially when combining with bortezomib. Combination treatment resulted in a synergistic growth inhibition, down-regulation of NF-κB DNA-binding activity, inhibition of cyclin D1, Bcl-xL, p-Akt, Akt, p-mTOR and p-Bad, up-regulation of Bax, and induction of cellular apoptosis [87] . In addition, this rGel/BAFF-mediated decrease in protein synthesis was associated with a decline in MCL-1 and XIAP proteins in CLL [88] . Taken together, the new class of targeted therapeutic agents may have therapeutic potential with a unique mechanism of action for malignant B-cells and may be an excellent candidate for clinical development. Further study should improve our ability to select BAFF/BAFF-R targeting therapies, to identify synergistic therapies and to determine which patients will benefit most from this intervention.

Table 1 Agents in development for autoimmune diseases and B-cell malignancies that target BAFF/BAFF-R.

Agents Target Current status
Belimumab [83] Human IgG1 monoclonal antibody against BAFF FDA-approved
LY2127399 [89] Human antibody to soluble and membrane BAFF Under clinic Phase III
Tabalumab [90] Anti-BAFF monoclonal antibody Under clinic Phase II
Briobacept [84] BAFF receptor fusion protein Completed clinic Phase I
A-623 [84] BAFF receptor fusion protein derived peptide with Fc Completed clinic Phase I
Anti-BR3 [85] Monoclonal antibody to BAFF-R In mice models
Bax345/BAFF [86] Fusion protein containing the truncated form of Bax linking to BAFF In malignant B cell lines
rGel/BAFF [88] Fusion toxin composed of rGel tether to BLyS In mice models of MCL

Conflict of interest

The authors declare no conflict of interest.

Reviewers

Dr. V. De Re, United of Clinical and Experimental Pharmacology, IRCCS – Centro di Riferimento Oncologico, National Cancer Institute, I-33081 Aviano, Pordenone, Italy.

Dr. Lukasz Bolkun, M.D., Ph.D., Medical University, Hematology, University Hospital, M.Sklodowska-Curie 24a, Bialystok 15-276, Poland.

Acknowledgments

This study was supported by National Natural Science Foundation of China (30971296, 81170488, 81370657), Natural Science Foundation of Jiangsu Province (BK2010584), Key Projects of Health Department of Jiangsu Province (K201108), Jiangsu Province's Medical Elite Program (RC2011169), Priority Academic Program Development of Jiangsu Higher Education Institute (JX10231801), National Public Health Grand Research Foundation (201202017), Development of Innovative Research Team in the First Affiliated Hospital of NJMU, and State Key Clinical Department construction.

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Dr. Jian-Yong Li is a professor and Director of Department of Hematology at the First Affiliated Hospital of Nanjing Medical University. He has a strong interest in clinical and basic study of lymphoid malignancies.

 

Dr. Wei Xu is a professor of Department of Hematology at the First Affiliated Hospital of Nanjing Medical University. She specializes in clinical hematology with a research focus in molecular biology of lymphoid malignancies. She also has a strong interest in developing novel strategies to improve the efficacy of lymphoid malignancies chemotherapy.

Footnotes

Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing 210029, China

lowast Corresponding author. Tel.: +86 25 83781120; fax: +86 25 83781120.