*2.2.1. Antigen-driven BCR activation and lymphomagenesis*

The hypothesis that antigenic stimulation can contribute to the development of B-cell malignancies was proposed over half a century ago [60]. There is growing indirect and direct evidence suggesting that antigen recognition may have a role in the pathogenesis of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphoma (MZL) of the spleen, and MZL of mucosa-associated lymphoid tissue (MALT)-type.

Indirect evidence for the role of antigen stimulation includes the association between certain lymphoma subtypes and specific infections and autoimmune diseases, as well as the identification of an antigen selection footprint in the BCR; i.e., a bias in gene usage and positive selection of somatic mutations in the complementarity determining regions [40, 42, 50, 61, 62]. More direct evidence for the role of antigen stimulation and BCR activation in lymphomagenesis is based on the identification of BCR reactivity toward foreign or auto-antigens, and the induction of intracellular BCR signaling in primary lymphoma cells in response to specific antigens [63–65].

Although several bacterial and viral infections have been associated with the development different lymphoma types, direct demonstration of lymphoma development due to infectious agent-derived antigenic stimulation remains limited.

*Helicobacter pylori* infection is associated with gastric MZL of MALT-type. This association relies on epidemiological, biological, molecular, and clinical data [41, 66–70]. Indeed, since the initial evidence of the association between *H. pylori* infection with the development of gastric MALT lymphoma [67], *H. pylori* eradication has established as the first-line therapy for this lymphoma [71, 72]. It has been demonstrated that MALT lymphoma B cells exhibit polyreactive surface BCR immunoglobulins. Direct stimulation by specific alloantigens (including *H. pylori* sonicate) and autoantigens recognized by these surface antibodies leads to the proliferation of tumor cells [73]. *H. pylori* infection may also induce aberrant AID expression followed by accumulation of mutations in tumor-related genes, suggesting a link between BCR activation and AID expression [74]. Nevertheless, a direct link to the activation of the BCR signaling pathway remains elusive.

*Chlamydia psittaci* infection is associated with ocular adnexal extranodal marginal zone lymphomas (OAEMZLs) [75]. These neoplasms express a biased repertoire of mutated surface immunoglobulins suggesting, which suggests that antigen receptors have been subject to clonal selection. In OAEMZL patients, local monocytes and macrophages are the carriers of *Chlamydia psittaci*, and lymphomas seem to preferentially arise in organs primarily exposed to antigens [76].

activation of a signaling complex that transmits the signal inside the cell. In contrast, the tonic

**Figure 2.** BCR signals generated in malignant and normal B cells. (A) Tonic signaling: random and transient disruptions in the equilibrium between positive regulators of BCR signaling, such as the CD79a/CD79b heterodimer, LYN and SYK, and negative regulators, such as the various phosphatases (PTP), could generate a tonic antigen-independent BCR signal characterized by increased activity of the PI3K/AKT pathway. (B) Aggregation of neighboring BCRs in polyreactive receptors initiates a cell-autonomous BCR signal in the absence of an external antigen. (C) The binding of the cognate antigen induces aggregation of neighboring BCRs that initiate the classical antigen-dependent BCR signal (see text for

Current evidence indicates that all three, tonic, autonomous, as well as antigen-dependent BCR signaling, are used by different B-cell lymphoid neoplasms. Activation may occur through physiological mechanisms such as antigen interaction or by pathological mechanisms such as mutations in genes acting downstream the signaling cascade. The relative contribution of these types of signals varies across different B-cell neoplasms and is currently

The hypothesis that antigenic stimulation can contribute to the development of B-cell malignancies was proposed over half a century ago [60]. There is growing indirect and direct evidence suggesting that antigen recognition may have a role in the pathogenesis of chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), marginal zone lymphoma (MZL) of

Indirect evidence for the role of antigen stimulation includes the association between certain lymphoma subtypes and specific infections and autoimmune diseases, as well as the identification of an antigen selection footprint in the BCR; i.e., a bias in gene usage and positive

the spleen, and MZL of mucosa-associated lymphoid tissue (MALT)-type.

signal occurs in the absence of external ligands (**Figure 2**) [58, 59].

*2.2.1. Antigen-driven BCR activation and lymphomagenesis*

subject to debate.

details).

24 Hematology - Latest Research and Clinical Advances

Certain lymphomas, such as splenic marginal zone lymphoma (SMZL), are associated with *hepatitis C virus* (HCV) infection. Current evidence suggests that a subset of HCV-associated lymphomas originate from B cells that were initially activated by the HCV-E2 protein, suggesting that this subgroup of lymphomas arise as an expansion of HCV-reactive B cells [77]. Consistently, antiviral treatment results in complete responses in about 75% of HCV positive lymphoma patients, whereas no responses are seen in HCV negative patients [78]. Altogether, this data suggest that antigen-dependent BCR activation may be the driver of lymphomagenesis for some SMZL cases; and removal of the antigen can lead to clinical remission in these patients.

Several viral, bacterial, and fungal antigens may bind specific BCRs on chronic lymphocytic leukemia (CLL) cells [79–81]. Moreover, CLL cells in the lymph node contain increased levels of activated SYK and express genes upregulated in response to BCR activation [82]. In addition, the observation of a reversible down-modulation of surface IgM expression on CLL cells also supports the idea of chronic antigen stimulation [83].

In follicular lymphoma (FL), the BCR is characterized by abnormal N-linked glycosylation. The mannosylated variable regions of FL immunoglobulins bind to recombinant lectin domains of the mannose receptor and dendritic-cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), which results in stimulation of FL cells [84]. It has also been demonstrated that V-region mannosylation conferred the ability of B cells to be activated by soluble bacterial lectins from common opportunistic pathogens such as *Pseudomonas aeruginosa* or *Burkholderia cenocepacia* while disrupting the initial receptor specificity for potential autoantigens [64].

*2.2.3. Autonomous signaling and lymphomagenesis*

the structural BCR backbone [102].

gene expression signature of ABC DLBCL.

*2.2.4. Mutations in the BCR signaling cascade*

in ABC DLBCL and CLL cases [105, 106].

[87, 99–101].

property.

Autonomous antigen-independent, BCR signaling is a survival mechanism characteristic of the pre–B-cell receptor [57, 98]. However, immature and mature B cells with BCRs, that recognize multiple self-antigens, may also induce autonomous signaling and selective expansion of B cell in a manner comparable to the pre-BCR [56]. This functional similarity between autoreactive BCRs and the pre-BCR suggests that recognition of self-antigens might not only play a role in the positive selection of early B cells, but also could contribute to lymphomagenesis

The Antigen Receptor as a Driver of B-Cell Lymphoma Development and Evolution

http://dx.doi.org/10.5772/intechopen.72122

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Autonomous signaling has been proposed as a novel oncogenic mechanism in chronic lymphocytic leukemia (CLL) and diffuses large B-cell lymphoma (DLBCL) [87, 100, 101]. BCR, derived from both mutated and unmutated CLL cases, expressed in a cellular system designed to measure BCR signaling cascade activation, show signaling properties that are equivalent to those of the pre-BCR [87]. This striking signaling property is dependent on the antigen-binding site of the clonal BCR and an internal motif in framework region 2, a part of

The gene expression profile of activated B-cell (ABC) type of DLBCL resembles that of mature B cells upon stimulation via their B-cell receptor (BCR). In up to 30% of ABC DLBCL cases, this signature can be explained by gain-of-function mutations in CD79A, CD79B, or CARD11 [103]. However, in patients without CARD11 mutations activation of the BCR may occur through autonomous signaling. We have recently demonstrated the presence of autonomous BCR activity in 72% of non-GCB DLBCL, including primary mediastinal DLBCL [100, 101]. This finding may provide a complementary or alternative explanation to the characteristic

These findings in CLL and DLBCL support the concept of the BCR acting as a true oncogene, despite being structurally normal and solely characterized by this autonomous signaling

In addition to the natural activation, BCR signaling can be induced by acquired mutations.

Different ABC DLBCL cases carry diverse activating mutations in the BCR pathway (**Table 1**). Mutations of a critical tyrosine residue in the ITAM of CD79B increase the signaling response by interfering with activation of LYN. In this subset of ABC DLBCL cells, PI3K and BTK signaling remain essential for NF-κB activation [104]. About 10% of ABC DBCL cases show activating mutations of CARD11, a key protein that connects BCR activation to NF-κB signaling. This mutation is sufficient to intrinsically activate survival signaling in the malignant B cells and obviates the need for upstream BCR signaling [103]. Loss of function mutations in the tumor suppressor A20 contributes to NF-κB pro-survival signaling have also been described

The source of the antigen is not necessarily derived from an external pathogen as it has also been shown to derive from self-antigens. CLL BCRs can react with many different self-antigens, including antigens released by apoptotic cells [85, 86]. In addition, BCR derived from CLL patients can bind to a conserved epitope within the second framework region (FR2) of their own BCR [87]. About 26% of FL cases recognize autoantigens, and the interaction with certain self-antigens such as myoferlin can induce BCR-mediated signaling *in vitro* [65]. It has also been demonstrated that interaction of the BCR of ABC DLBCL with a self-antigen is essential for the survival of these lymphoma cells. This interaction may explain the microclusters observed in the plasma membrane of ABC DLBCL cells [5, 88].
