Abnormalities of the Immune System Induced by Dysregulated bcl-2 Expression in Transgenic Mice

Abstract

Dysregulated expression of the putative cellular oncogene bcl-2 by chromosomal translocation has been strongly implicated in follicular center B cell lymphoma, one of the most common hematologic malignancies in humans. These tumors usually contain a 14;18 chromosomal translocation (Fukuhara et al 1979) that juxtaposes bcl-2 with the immunoglobulin heavy chain (Igh) locus (Tsujimoto et al 1984; Cleary and Sklar 1985; Bakshi et al 1985). The recombination presumably subjects bcl-2 to the control of Igh regulatory sequences which enforce its constitutive expression in B lymphoid cells. The bcl-2 gene encodes a 24 kD non-glycosylated protein located on the cytoplasmic face of the plasma membrane (Tsujimoto et al 1987; Chen-Levy et al 1989). It is normally expressed in pre-B cells, quiescent in resting B cells, expressed again in activated B cells and then downregulated upon their terminal differentiation (Reed et al 1987; Gurfinkel et al 1987; Chen-Levy et al 1989). The first indication of the function of this putative oncogene was revealed by our previous studies on interleukin-3-dependent cell lines infected with a bcl-2 retrovirus. The cells survived withdrawal of growth factor, but entered a Go state, suggesting that constitutive bcl-2 expression promotes cell survival rather than proliferation (Vaux et al 1988).