Introduction

The most recent WHO Classification of Lymphoid Neoplasms describes more than 40 entities that originate from cells in the lymphoid organs at various stages of normal lymphocyte differentiation (1). Of these, ~90% derive from mature B cells, including B-cell non-Hodgkin lymphoma (B-NHL) and Hodgkin lymphoma (HL), while the remaining 10% derive from T-cells and natural killer cells (T-NHL). To date, most of the recurrent genetic alterations involved in the pathogenesis of B-NHL have been identified and, for many of them, the ability to promote lymphomagenesis has been documented in animal models. Conversely, little is known about the pathogenesis of T-NHLs, due to their uncommon occurrence and biological heterogeneity. This chapter will provide an overview of the most common B- and T-NHLs, with emphasis on their molecular pathogenesis.

B-cell development

The development of mature B lymphocytes from hematopoietic stem cells is regulated by the sequential rearrangement of the immunoglobulin (Ig) genes, together with the acquisition or loss of expression of specific proteins. B-cell precursors first rearrange their Ig heavy (IgH) and light chain (IgL) loci in the bone marrow, through the process of V(D)J recombination (2). If successful in completing this process, cells expressing a functional surface B-cell receptor (BCR) will migrate to secondary lymphoid organs as mature, naïve B-cells. Upon T-cell-dependent antigen stimulation, activated B cells can either differentiate directly into antibody-secreting cells, or start proliferating at high rates and form a characteristic structure known as germinal center (GC; Figure 68.1; 2,3). This structure can be schematically compartmentalized into a dark zone, where proliferating centroblasts diversify their Ig variable region (IgV) genes by the process of somatic hypermutation (SHM), to increase antibody affinity for the antigen, and a light zone, where non-dividing centrocytes undergo Ig class-switch recombination (CSR) and are selected based on their ability to produce high-affinity antibodies (Figure 68.1; 3–6). Cells with low affinity towards the antigen are eliminated by apoptosis. Both SHM and CSR require DNA strand breaks and depend on activation-induced cytidine deaminase (AID), which plays a central role in the generation of genetic alterations in most B-NHL (7–9).