INSIGHTS FROM TRANSGENIC MICE REGARDING THE ROLE OF BCL-2 IN NORMAL AND NEOPLASTIC LYMPHOID-CELLS

The bcl-2 gene was first discovered by molecular analysis of the 14;18 chromosome translocation which is the hallmark of most cases of human follicular lymphoma. To date, it is unique among proto-oncogenes beca use, rather than promoting cell proliferation, it fosters cell surviva l. This review summarizes the impact of constitutive bcl-2 expression on the development and function of lymphocytes as well as their malign ant transformation. Expression of a bcl-2 transgene in the B lymphoid compartment profoundly perturbed homeostasis and, depending on the gen etic background, predisposed to a severe autoimmune disease resembling human systemic lupus erythematosus. T lymphoid cells from bcl-2 trans genic mice were remarkably resistant to diverse cytotoxic agents. Neve rtheless, T lymphoid homeostasis was unaffected and tolerance to self was maintained. Expression of high levels of Bcl-2 facilitated the dev elopment of B lymphoid tumours but at relatively low frequency and wit h long latency. Co-expression of myc and bcl-2, on the other hand, pro moted the rapid onset of novel tumours which appeared to derive from a lympho-myeloid stem or progenitor cell. Introduction of the bcl-2 tra nsgene into scid mice facilitated the survival and differentiation of pro-B but not pro-T cells, suggesting that a function necessary to sup plement or complement the action of Bcl-2 is expressed later in the T than the B lineage. Crosses of the bcl-2 transgenic mice with p53(-/-) mice have addressed whether loss of p53 function and gain of bcl-2 fu nction are synergistic for lymphoid cell survival.