**2.2. Pathogenic activation of the B-cell receptor signaling cascade**

We have recently described that, in IgM expressing FL, the mutation load of the Ig genes can be described as a function of the AID expression level. In contrast, in FL cases that underwent class switch recombination (i.e., IgG expressing lymphomas) AID expression and SHM of immunoglobulin genes are dissociated [40, 41]. The distinctive patterns induced by SHM may

**Figure 1.** Molecular mechanism of somatic hypermutation (SHM). AID requires a single strand to initiate the SHM process. Transcription by RNA polymerase II (RNA Pol II) exposes the single-stranded DNA template for AID. AID deaminates a cytosine to create an uracil, which can then be processed by different pathways. Replication over the uracil results in C to T or G to A transition mutations. Processing by uracil DNA glycosylase (UNG) generates an abasic site (Φ) that is cleaved by the apurinic/apyrimidinic endonuclease (APE1), which removes this site and then Polβ resynthesizes the DNA. Recognition of the U-G mismatch by MutSα (represented by a torus shape) followed by the action of Exo1 and Polη spreads mutations (indicated as "N") to surrounding A-T nucleotides. UNG and Msh2/Msh6 can also act in the context of high fidelity base excision repair (BER) and mismatch repair (MMR) pathways, which results in error-free

also have implications for the clinical evolution of the disease [42].

repair.

22 Hematology - Latest Research and Clinical Advances

Antibody molecules, when expressed on the cell surface, constitute the binding moiety of a molecular complex known as B-cell antigen receptor (BCR). Signals from the BCR regulate the development and function of B cells. However, the ability of the BCR signaling pathway to induce cell survival and proliferation could be adopted and distorted by malignant cells.

The BCR immunoglobulin consists of a heavy chain and a light chain, whereas its precursor, the pre-BCR, consists of a heavy chain and a surrogate light chain. The transmembrane domain of the heavy chains anchors the BCR to the cell membrane, where each BCR molecule associates with the signaling subunit. The signaling subunit is constituted by a heterodimer of Igα (CD79A) and Igβ (CD79B) [51]. Within their cytoplasmic tails, Igα and Igβ harbor 2 conserved tyrosine residues as part of a 26 amino acid-long sequence, also referred to as an immunoreceptor tyrosine-based activation motif (ITAM) [52]. Phosphorylation of ITAM through kinases, such as Lck/Yes-related novel protein tyrosine kinase (LYN), B-lymphoid kinase (BLK), or spleen tyrosine kinase (SYK), marks the first step in signal transduction from the BCR to the nucleus [53]. SYK in conjunction with PI3K recruits Burton's tyrosine kinase (BTK). Upon activation of the BCR pathway, BTK binds to PIP3 and attaches to the plasma membrane [54]. These events contribute to BCR-induced calcium release, cell proliferation, and activation of the NF-κB pathway (**Figure 2A**) [55].

In pre-B cells, the BCR signaling cascade is activated through autonomous signaling, a mechanism that relies on the structural conformation of the pre-BCR which is constituted by a heavy chain and a surrogate light chain [56, 57]. While pre-B cells rely on autonomous BCR signaling, immature and mature B-cells receive two types of signals from their BCRs: the antigen-dependent, and the antigen-independent "tonic" signals. The antigen-dependent signal is generated by binding of an external antigen to the BCR and results in the clustering and

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

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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Although several bacterial and viral infections have been associated with the development different lymphoma types, direct demonstration of lymphoma development due to infectious

*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

*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

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

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

In follicular lymphoma (FL), the BCR is characterized by abnormal N-linked glycosylation. The mannosylated variable regions of FL immunoglobulins bind to recombinant lectin

also supports the idea of chronic antigen stimulation [83].

antigens [63–65].

to antigens [76].

patients.

agent-derived antigenic stimulation remains limited.

signaling pathway remains elusive.

**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 details).

activation of a signaling complex that transmits the signal inside the cell. In contrast, the tonic signal occurs in the absence of external ligands (**Figure 2**) [58, 59].

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 subject to debate.
