*2.1.1. V(D)J recombination*

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

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 effi-

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

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 correspond-

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 muta-

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

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

be adopted by malignant B-cell, and even become essential for their survival [5].

**2. Major B-cell receptor–related lymphomagenic mechanisms**

**2.1. Genetic mechanisms that create a functional antigen receptor and their errors** 

Three unique genetic mechanisms operate sequentially in various stages of B-cell development to generate a functional antigen receptor: VDJ recombination, class switch recombination (CSR), and somatic hypermutation (SHM). Errors during these events may lead to

or surface-bound antigens.

18 Hematology - Latest Research and Clinical Advances

intrinsic oncogenic risk [2].

cascade.

**leading to oncogenic events**

lymphomagenesis.

caciously upon re-exposure to the evoking antigen [1].

ingly precursor cell from mature B-cell lymphomas.

tions creates almost random point mutations [2–4].

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

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 rearrangement of the light chain [7].

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

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