B-Cell Receptor Signaling in the Genesis and Maintenance of B-Cell Lymphoma

Abstract

Lymphomas constitute a number of different diseases that have been subdivided into two broad categories, Hodgkin’s and non-Hodgkin’s lymphoma (NHL). Hodgkin’s disease comprises a uniform set of malignancies primarily defined by the presence of Reed–Sternberg giant cells, whereas NHL is a heterogeneous set of clinical entities. The number of cases of NHL is almost tenfold that of Hodgkin’s disease [1]. In addition, the number of newly diagnosed cases of NHL has increased by almost 80% in the last 25 years. This dramatic increase does not correlate with age, gender or infectious agents, and cannot be accounted for by the onset of HIV-associated B-cell lymphomas [2]. As a result, NHL are currently the fifth most common form of cancer in the USA, after breast, prostate, lung and colon cancer [101]. NHL is one of the few cancers whose incidence and mortality rates have risen in the past 35 years. Despite the increase in the incidence of NHL, the etiology of these lymphomas remains elusive, and current therapeutic approaches rely on traditional, nonspecific chemotherapeutic approaches. The diagnosis of NHL encompasses different clinical entities. Approximately 85–90% of all NHL in the USA consist of B-cell lymphomas [3]. Among the B-cell NHLs, aggressive lymphomas account for 45–50% of new diagnoses. The two most common forms of aggressive NHL are diffuse large B-cell lymphoma and Burkitt’s lymphoma. These two types of malignancies involve neoplastic B cells that have a surface phenotype that is consistent with that of mature, activated B cells. Specifically, they express B-cell antigen receptors (BCR) on their surface, which contain mutations consistent with the process of affinity maturation during a germinal center reaction [4]. These cells also express other molecules that are normally expressed by postgerminal B cells [5]. There are other B-cell NHLs that have a similar cellular composition. These include follicular lymphomas, mucosal-associated lymphoid tissue lymphomas and mantle-cell lymphomas [3]. All of these B-cell NHL share a B-cell surface phenotype, including BCR expression. The nature of additional mutations, possibly involving oncogenes and tumor suppressor genes, has been postulated to explain their biological differences [6]. The one characteristic they have in common, namely BCR expression and evidence of antigen-dependent activation, may suggest that the BCR and an antigen may have an important role in the genesis of these tumors. Dameshek and Schwartz originally proposed that antigenic stimulus could contribute to the development of lymphomas nearly 50 years ago [7]. Throughout the years, a large amount of circumstantial evidence has implicated chronic inflammation in lymphomagenesis. There are prior hints that antigenic stimulus can play a role in lymphomagenesis. First, retroviral infection of mice elicits T-cell lymphomas only in those strains of mice that can mount an immune response to the virus [7,8]. Second, infection with Helicobacter pylori is an apparent cause of human lymphomas in mucosal-associated lymphoid tissue and gut-associated lymphoid tissue [9]. Treatment with antibiotics to eradicate infection elicits remission of these tumors, as if they might have been sustained by antigenic stimulus from the microbe [10,11]. Third, mice with graft versus host disease consequent to bone marrow transplantation frequently develop T-cell lymphomas; immunosuppression of the mice prevents the tumors [12]. Fourth, chronic antigenic stimulation by infection may contribute to the genesis of Burkitt’s lymphoma [13,14]. Fifth, the gene-expression profiles of diffuse large B-cell lymphomas resemble those of B cells that have mounted a response to antigen [15], and the tumor cells display high-affinity antigen receptors on their surface, as if they had been subjected to the selective pressure of an antigen [4,16–18]. Sixth, our own studies demonstrate a causal relationship between BCR-derived signals and elevated levels of MYC in the genesis of B-cell lymphomas in mice [19]. These findings prompt the hypothesis that an antigenic stimulus may cooperate with other tumorigenic influences in the genesis of lymphoma.