Origin and Pathogenesis of B Cell Lymphomas

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.

Pathogenesis beyond the cancer clone(s) in multiple myeloma

“…3 The observation that patients with premalignant PC dyscrasia monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM) also carry these initial mutations suggests that they are necessary, but not sufficient, in MM pathogenesis. Late oncogenic events are thought to occur in the BM, after the founder cancer clone is completely differentiated into a long-lived PC (Figure 1).…”

“…1,2 Based on the sequencing of the immunoglobulin heavy chain (IgH) variable region of MM cells (MMCs), the first oncogenic events in MM appear to occur in the germinal center, likely during the processes of isotype class switching and somatic hypermutation, which are, by nature, mutation prone. 3 The observation that patients with premalignant PC dyscrasia monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM) also carry these initial mutations suggests that they are necessary, but not sufficient, in MM pathogenesis. Late oncogenic events are thought to occur in the BM, after the founder cancer clone is completely differentiated into a long-lived PC ( Figure 1).…”

“…Based on karyotype, MM is classified as nonhyperdiploid and hyperdiploid, with the latter accounting for 50% to 60% of cases and characterized by trisomies in odd chromosomes (3,5,7,9,11,15,19, and 21). In contrast, nonhyperdiploid MMCs harbor translocations between 14q32, the locus of IgH, and one of several partner oncogenes like MAF (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog), MAFB, MM SET domain (MMSET), fibroblast growth factor receptor 3 (FGFR3), and cyclins D1 and D3.…”

Monoclonal IgG in MGUS and multiple myeloma targets infectious pathogens

“…lymphocytic leukemia (8)(9)(10)(11). Malignant transformation may occur directly via B cell infection and transformation, or indirectly via chronic Ag-driven stimulation of the B cell receptor (BCR) that has identical heavy and light chain specificity for secreted mc Ig.…”

Identification of MEF2B , EBF1 , and IL6R as Direct Gene Targets of Epstein-Barr Virus (EBV) Nuclear Antigen 1 Critical for EBV-Infected B-Lymphocyte Survival

“…This form of persistent infection, referred to as EBV latency, is capable of transforming the growth, differentiation, and survival properties of the host cell. Several EBV latency genes have been implicated in the carcinogenic transformation of host cells, suggesting that the mechanisms of EBVinduced cancer are diverse and complex (5)(6)(7).…”