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William C, Neri A, Baldini L, Chaganti RSK,. Klein U, Küppers R, ... Liu YJ, Joshua DE, Williams GT, Smith CA,. Gordon J .... LH, Lerach S, Tang H, Ma J, Rossi D,.
Chapter 1 Origin and Pathogenesis of B Cell Lymphomas Marc Seifert, René Scholtysik, and Ralf Küppers Abstract Immunoglobulin (Ig) gene remodeling by V(D)J recombination plays a central role in the generation of normal B cells, and somatic hypermutation and class switching of Ig genes are key processes during antigen-driven B cell differentiation. However, errors of these processes are involved in the development of B cell lymphomas. Ig locus-associated translocations of proto-oncogenes are a hallmark of many B cell malignancies. Additional transforming events include inactivating mutations in various tumor suppressor genes, and also latent infection of B cells with viruses, such as Epstein–Barr virus. Many B cell lymphomas require B cell antigen receptor expression, and in several instances chronic antigenic stimulation plays a role in sustaining tumor growth. Often, survival and proliferation signals provided by other cells in the microenvironment are a further critical factor in lymphoma development and pathophysiology. Many B cell malignancies derive from germinal center B cells, most likely because of the high proliferation rate of these cells and the high activity of mutagenic processes. Key words: B cells, B cell lymphoma, Clonality, Chromosomal translocation, Germinal center, Hodgkin’s lymphoma, Immunoglobulin genes, V gene recombination, Somatic hypermutation

1. B Cell Development and Differentiation 1.1. Introduction

B cells are lymphocytes that confer efficient and long-lasting adaptive immunity by the generation of high-affinity antibodies against antigens. These cells form an essential part of the humoral immune response and play a central role in immunologic memory. Beyond this, B lymphocytes participate in a broad range of immunological functions, including antigen presentation, immune regulation, and provision of a cellular and humoral pre-immune repertoire. Their contribution to the immune system is complex and multilayered.

Ralf Küppers (ed.), Lymphoma: Methods and Protocols, Methods in Molecular Biology, vol. 971, DOI 10.1007/978-1-62703-269-8_1, © Springer Science+Business Media, LLC 2013

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1.2. B Cell Diversity and Antibody Structure

All mature B cells express a membrane-bound antibody with individual specificity. This immunoglobulin (Ig) is associated with cofactors, and together these molecules form the B cell receptor (BCR). The cofactors immunoglobulin alpha and beta (Igα/Igβ) participate in signal transduction of this surface receptor. The diversity of immunologically competent B cells results from the variability of their BCR. This is a consequence of recombination processes during B lymphocyte development in which gene segments located in the Ig loci are joined to give rise to new and individually generated Ig genes. Antibodies are composed of four polypeptides, two identical heavy chains (IgH) and two identical light chains (IgL), that are linked by disulfide bonds. The IgL chains are of either κ or λ isotype. All these polypeptides consist of a carboxyterminal constant (C) and an aminoterminal variable (V) fragment. The V region includes four framework regions, each separated by hypervariable regions, the complementarity determining regions 1, 2, and 3 (CDRI to CDRIII). Whereas the VH region gene is generated by the recombination of three independent gene segments, the variable (VH), diversity (DH), and joining (JH) segments, the light-chain V region genes are composed of only two segments, namely, the VL and JL segment (1). The somatic recombination of these segments is catalyzed by the enzymes RAG1 and RAG2. These enzymes recognize recombination signal sequences flanking the gene segments, cut the DNA at these sites, and build hairpin structures at the coding ends (2). The hairpin structures can be resolved in different ways to generate (palindromic) P elements. Moreover, exonucleases can act arbitrarily to remove nucleotides from the ends of the rearranging gene segments. The enzyme terminal deoxynucleotidyltransferase (TdT) randomly adds (non-germline-encoded) N nucleotides to the ends of the rearranging gene segments before they are joined, and DNA repair factors finally complete the recombination process (1).

1.3. B Cell Development and Differentiation

The development of B cells is initiated in the fetal liver and relocated to the bone marrow during maturation of mammalian embryos. Throughout the differentiation processes, the microenvironment of the respective tissues (the microenvironmental niche) plays an essential role in providing nutrition, survival, and developmental stimuli. Multipotent hematopoietic stem cells give rise to lymphoid precursors that initiate an irreversible differentiation program. The development of B cells from lymphoid precursors is orchestrated by several key transcription factors that determine B cell fate. Early B cell factor 1 (EBF1), E2A, and PAX5 are the three main transcription factors for early B cell development (3). The production of a functional and unique BCR through V(D)J recombination is the central process for the generation of a mature B cell (4). Hence, selection processes for appropriate receptor molecules play a key

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role during B cell development, as nonfunctional or autoreactive B cells have to be eliminated. B cell development is regulated by an ordered rearrangement of antigen receptor gene segments, and can be divided into distinct steps according to the rearrangement status of the Ig loci and phenotypical features. The initial step in B cell development is a DH-to-JH gene rearrangement at the IgH locus on human chromosome 14. In humans, 27 DH segments and six JH gene segments are available for this rearrangement (Fig. 1) (5, 6) that can occur on both alleles. B lymphocyte precursors carrying DHJH joints are called pro B cells. Subsequently, one of about 120 VH segments is rearranged to the DHJH joint (Fig. 1) (7). The newly generated VH chain is expressed and paired to a surrogate light chain. The so formed pre-BCR is tested for functional competence. If functional, recombination processes of the second allele are suppressed (allelic exclusion), and the B lymphocyte precursor reaches the stage of the pre-B cell (4, 8). However, there are several possibilities to generate a nonfunctional pre-BCR: e.g., one of approximately 80 nonfunctional VH segments encoded in the human genome can be recombined to the DHJH joint (7). As well, nucleotide insertions or deletions occurring during the rearrangement process can cause frameshifts of the IgH gene, or the expressed VH chain cannot bind properly to the surrogate light chain and fails to form a stable pre-BCR. In case of a nonfunctional pre-BCR, a rearrangement of the second IgH allele or the potential use of V-gene replacement (recombination of further upstream located VH gene segments to the existing VHDHJH joint) is an alternative for the B lymphocyte precursor to generate a functionally competent pre-BCR (9). In case these escape-mechanisms are unsuccessful, the respective B lymphocyte precursor will undergo apoptosis (10). Only those B cell precursors that survive the selection for a functional pre-BCR start rearranging VL-to-JL light-chain genes in order to generate an immunoglobulin light chain. Light chain recombination starts at the κ loci on chromosome 2. In the human, depending on the haplotype, 30–35 functional Vκ gene segments and five Jκ segments are available for recombination (11, 12). In case of nonfunctional Vκ rearrangements on both alleles, the λ loci on chromosome 22 can be rearranged subsequently with 30–37 functional Vλ and four Jλ gene segments available (13, 14). B cells express either κ or λ light chains, a phenomenon called isotype exclusion. Only in very rare instances (