Cellular and molecular bases of B-cell clonal expansions.

The concept that lymphomagenesis is a multistep process is now widely accepted. Various factors are involved in the development and malignant progression of B-cell lymphoproliferative disorders. The most frequently recognized alterations in these disorders are chromosomal translocations which lead to the activation of proto-oncogenes (c-myc) or genes encoding for proteins involved in the control of the cell cycle (cyclin D1), differentiation (bcl-6) and apoptosis (bcl-2). In addition, genetic changes that inactivate tumor suppressor genes (p53, Rb, p16) have recently been identified. Infectious agents may also play a role in lymphomagenesis either by directly driving B-cell proliferation (EBV) or by inducing a chronic antigenic stimulation (EBV, HCV, HBV, helicobacter pylori). Finally, several data indicate that local cytokine networks and, in particular, autocrine (IL-6, IL-10) and/or paracrine (IL-2, IL-4, IL-6) loops probably play a contributory role in the development and evolution of B-cell lymphoproliferation. In the last few years, the advent of molecular biology techniques has allowed important advances in the definition of the events involved i the earlier phases of lymphoma development. This has been made possible, in particular, by the study of a series of oligoclonal or monoclonal lymphoproliferative disorders characterized by an indolent or "smoldering" clinical course, such as follicular lymphoma and the lymphoproliferation associated with autoimmune diseases, which are at high risk of evolution to a highly malignant lymphoma. In nearly all of these conditions, the clonal B-cells responsible for the early stages of the disease are probably not fully transformed and retain various degrees of responsiveness to a wide variety of microenvironmental stimuli (antigen or autoantigen stimulation, interactions with "reactive" T lymphocytes, local cytokine networks). These latter in turn may induce the regression of pathological lesions, maintain the disease in an active state or contribute to the evolution towards an overtly malignant lymphoma. These findings open new avenues for the design of unconventional strategies of intervention aimed at preventing the malignant evolution of pre-lymphomatous lesions and controlling the clinical course of certain low-grade B-cell lymphomas.