Lymphoma and the Control of B Cell Growth and Differentiation

Abstract

It is now widely accepted that lymphomagenesis is a multistep transformation process. A number of genetic changes and environmental and infectious factors contributing to the development and malignant progression of B-cell lymphoproliferative disorders are well documented. Reciprocal chromosomal translocations involving the immunoglobulin loci are a hallmark of most mature B cell lymphomas and lead to dysregulated expression of proto-oncogenes (c-myc) important for cell proliferation or genes involved in cell cycle progression (cyclin D1), differentiation block (bcl-6, PAX5) and cell survival (bcl-2, NF-kappaB). In addition, genetic alterations that inactivate tumor suppressor genes (p53, p16) have been frequently detected in some lymphoma tissues. Many of these genes are normally regulated by signals from the B cell antigen receptor. The high prevalence of bacterial and viral infection in lymphoma patients supports the hypothesis that infectious agents may play a contributory role in the development and evolution of B cell lymphoproliferative disorders by either directly inducing polyclonal B cell hyperactivation (EBV, HCV), or providing a chronic antigenic stimulus (EBV, HCV, HBV, H. pylori), or mimicking B cell antigen receptor signaling (EBV, HCV, HHV8), although whether these are causative factors or they are secondary to genetic changes in lymphomagenesis remains to be defined. Stimulatory signals from reactive T cells, local cytokines and growth factors can also contribute, to some extent, to the progression of transformation. Modulation of B cell antigen receptor signaling therefore emerges as a potentially powerful strategy for controlling the growth of certain B cell lymphomas.

Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target

“…5 However, unlike in BL tumors, E-MYC mice develop lymphoid tumors consisting of pre-pro-B cells lacking BCR expression that do not resemble NHL, but rather acute lymphoblastic leukemia (ALL). 6,7 In contrast, circumstantial evidence links chronic antigenic stimulation through the BCR to the development of certain B-cell NHLs, 2,8 and our own work has demonstrated direct contributions of antigen and the antigen receptor in a transgenic mouse model. 6 We have developed novel murine models of NHL that demonstrate the cooperation between BCR-derived signals and MYC overexpression during B-cell lymphomagenesis.…”

Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16 INK4A and p14 ARF expression

“…EBNA2 is expressed first and strongly up-regulates MYC (48-50). MYC induces cyclin D2, and cyclin D2-enforced cell cycle entry likely induces CDKN2A p16 and p14 expression (48)(49)(50)(51)(52). CDKN2A p16 INK4A and p14 ARF are partially regulated by different promoters and have different first exons (exon 1α for p16 INK4A and 1β for p14 ARF ), but share exons 2 and 3 (53,54).…”

Stimulation of c-Myc Transcriptional Activity by vIRF-3 of Kaposi Sarcoma-associated Herpesvirus

“…c-myc is a proto-oncogene that has been implicated in controlling cellular growth, proliferation, and cell survival (24). It also plays a critical role in the development of B-cell lymphomas (25)(26)(27). Overexpression of c-myc, as a consequence of a reciprocal chromosomal exchange involving the immunoglobulin loci, can be seen in Epstein-Barr virus-positive B-cell lymphomas.…”