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

**The Antigen Receptor as a Driver of B-Cell Lymphoma** 

DOI: 10.5772/intechopen.72122

Julieta Sepulveda, Noé Seija, Pablo Oppezzo and Marcelo A. Navarrete Marcelo A. Navarrete Additional information is available at the end of the chapter

Julieta Sepulveda, Noé Seija, Pablo Oppezzo and

Additional information is available at the end of the chapter

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

#### **Abstract**

The expression of a functional antigen receptor is necessary for cell survival of normal B lymphocytes and most B-cell neoplasms alike. When the genetic modifications of the B-cell receptor locus fail to produce a functional antigen receptor or result in deleterious mutations of a previously expressed receptor, the affected B cell will undergo apoptosis. The three physiological mechanisms that generate the B-cell receptor, VDJ recombination, somatic hypermutation, and class switch recombination, can induce double-strand DNA breaks and can specifically contribute to lymphomagenesis. On the other hand, the B-cell receptor activation and signaling pathways, which provide strong survival and proliferation signals to normal B cells, can support the growth and evolution of malignant lymphocytes. As a result, an otherwise structurally normal B-cell receptor can behave, from the functional perspective, as a true oncogene. In this chapter, we provide an in-depth discussion of the most recently discovered recurrent mechanisms involving the B-cell receptor in lymphoma pathogenesis. The discussion is structured around two major topics: (1) the genetic mechanisms that create a functional antigen receptor and their errors leading to oncogenic events, and (2) the pathogenic activation of the B-cell receptor signaling cascade. Finally, we will briefly comment on novel emerging therapies targeting the B-cell receptor at different levels.

**Keywords:** lymphoma, B-cell receptor, activation-induced deaminase (AID), somatic hypermutation, class switch recombination, lymphomagenesis, pathogenesis, oncogenesis

#### **1. Introduction**

The immune system has evolved with the primary purpose of eliminating or at least controlling invading pathogens. In contrast to innate immunity, the adaptive immune system relies

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

for this task on recognition of the pathogen through antigen-specific receptors. In the case of B cells, these receptors are membrane-bound or soluble immunoglobulins that engage soluble or surface-bound antigens.

*2.1.1. V(D)J recombination*

a part of a structure known as pre–B-cell receptor.

continue with the rearrangement of the Ig-Lambda locus [8].

may result in DNA repair or induction of apoptosis [11].

rearrangement of the light chain [7].

*2.1.2. Class switch recombination*

In the germ line DNA configuration, the antigen receptor gene loci contain discontinuous, nonfunctional V, D, and J segments. Committed B lymphocyte precursor cells create functional immunoglobulin heavy and light chain genes through VDJ recombination and VJ recombination, respectively [6]. The V(D)J recombination starts at the pro-B cell stage by activation of recombination-activating genes (RAG) 1 and 2. The first step is the DJ joining in the IgH locus followed by the joining of V segments to DJ, resulting in the rearrangement of the μ-chain (μH). The μH paired with a surrogate light chain (SLC) is expressed on the cell membrane as

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

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

19

In pre-B cells, RAG1/2 expression results in the recombination of the kappa light chain. A successful rearrangement will induce RAG downregulation; otherwise, RAG will start a second

During V(D)J recombination, a successful rearrangement of the heavy chain will suppress the rearrangement of the second allele, a process known as allelic exclusion. In the case of Ig-Kappa chains, if neither of both alleles generates a productive receptor the process will

V(D)J recombination can be divided into two phases: the cleavage phase and the joining phase. In the cleavage phase, RAG1/2 creates double-strand breaks (DSB) at recombination signal sequences (RSS), which are located at the start of each antigen receptor gene segment. RSS is composed by a heptamer, a spacer sequence (12–23 nucleotides) and a nonamer sequence. RAG acts on RSS by introducing a nick between the coding sequence and the heptamer [9]. At each of the two remaining ends, called the coding ends, the two strands of DNA are joined to form a hairpin structure. The Artemis nuclease nicks the hairpin, whose ends are then joined by non-homologous end joining (NHEJ) [10]. The recombination process activates the DNA damage response (DDR), a system that detects any signal of DNA damage. The action of DDR

Class switch recombination (CSR) is a process that replaces the default Cμ exons with exons from a downstream constant chain (Cα, Cϵ, or Cγ), resulting in a change from IgM expressed

CSR occurs by intrachromosomal deletion and recombination events between two different switch (S) regions localized upstream of each constant region in the IgH locus. S regions are GC-rich with a high frequency of the WGCW (A/T-G-G-A/T) motif, which is a target of activation-induced deaminase (AID) activity. CSR has two phases: (1) the break at the donor and

The recombination is initiated by AID, an enzyme that deaminates cytosines into uracil at the donor and acceptor S regions. Subsequently, the base excision repair (BER) pathway creates a single strand break (SSB) that is processed to double strand breaks (DSB) by mismatch repair

by naïve B cells to expression of one of the downstream isotypes IgA, IgG, IgE.

acceptor S regions, and (2) the ligation process between distal breaks [12].

Hallmarks of the adaptive immune system related to the B-cell receptor are: (1) continuous presence of an extremely broad repertoire of antigen receptors; (2) rapid activation and expansion of cells whose particular receptors recognize a given antigen, and (3) maintenance of a memory of every immune response that has taken place in order to react even more efficaciously upon re-exposure to the evoking antigen [1].

The immune system has, therefore, developed unique molecular mechanisms to generate virtually unlimited numbers of antigen receptors with different specificities. These mechanisms are V, D, and J recombination of immunoglobulin gene segments, class switch recombination, and somatic hypermutation (SHM). Since these events involve genome editing, they entail intrinsic oncogenic risk [2].

The expression of a functional B-cell receptor (BCR) on the cell surface after successful completion of VDJ recombination distinguishes precursor from mature B cells, and correspondingly precursor cell from mature B-cell lymphomas.

Upon antigen recognition, B cells can undergo antibody affinity maturation through SHM, a genetic mechanism that permits antibody diversification. SHM is mediated by activationinduced deaminase (AID), an enzyme physiologically expressed in the germinal center. AID converts C:G base pairs in immunoglobulin genes into U:G mismatches. Repair of these mutations creates almost random point mutations [2–4].

Signals generated by the BCR govern the development, function, and survival of normal B cells. However, its ability to efficiently activate anti-apoptotic and proliferation pathways can be adopted by malignant B-cell, and even become essential for their survival [5].

In the current chapter, the discussion is structured around two major pathogenic mechanisms: (1) genetic mechanisms that create a functional antigen receptor and their errors leading to oncogenic events, and (2) pathogenic activation of the B-cell receptor signaling cascade.
