B-cell neoplasia in a developmental framework

The development and differentiation of B-lymphocytes has a number of unusual features. One of them stems from the rearrangement of the immunoglobulin genes and the generation of antibody diversity. The ability of the cognate antigen to activate and to trigger the clonal expansion of B-cells that carry a complementary surface immunoglobulin receptor, is another. Rapid apoptotic death of the non-activated lymphocyte is a third. The reversible shift between resting and activated states and the maintained ability of the fully differentiated plasma cell to divide are some of the relevant consequences. Tumor development can be directly related to the disruption of this life cycle at one point or another. EBV-induced activation of resting B-cells into immunoblasts endows the target cells with unlimited growth potential, as shown by their immortalization in vitro. This is normally counteracted by the immune surveillance of the host, shaped by the selective power of our coexistence with the virus over millions of years. Congenital, iatrogenic or virus (HIV)-induced immunodeficiency may permit the development of progressive lymphoproliferative disease. Interference with the normal apoptotic death program by the accidental juxtaposition of the bcl-2 gene to an immunoglobulin locus may cause low grade lymphoma. The corresponding juxtaposition of c-myc, a proliferation stimulating oncogene, can trigger the development of a high grade lymphoma, but probably only after additional mutations. Similar Ig/myc juxtaposition may occur in specific mesenteric or intraintestinal plasma cell populations or their precursors in mice and rats and lead to plasmacytoma development. All Ig/myc translocations act by preventing the carrier cell from leaving the cycling compartment. Neoplasia can thus be seen as a disturbance of normal developmental programs. Depending on environmental and/or genetic predisposition, accidents of gene displacement and specific vulnerabilities of the preneoplastic cell, the phenotypic properties of the tumor and the degree of its malignancy can be placed in a comprehensible biological framework.