Owing to its lineage and differentiation stage-restricted expression, CD77 has been mooted as a therapeutic target in Burkitt lymphoma (BL). The recognition that the globotriaosyl moiety of this neutral glycosphingolipid is a receptor for Escherichia coli-derived Verotoxin-1 (Shiga-Like Toxin-1) offers a potential delivery system for the attack. Here we show that CD77-expressing Group I BL cells which are normally susceptible to activation-induced death on binding Verotoxin-1 B chain are protected in the presence of CD40 ligand. Ectopic expression of either bcl-2 or bcl-x L also afforded resistance to the actions of the B chain. In total contrast, neither of the survival genes nor a CD40 signal ± even when acting in concert ± protected against killing mediated by the holotoxin. These findings indicate that while therapeutic modalities for CD77-expressing B cell tumors (which include follicular lymphoma) based on the use of Verotoxin-1 B chain might be compromised by the activation of endogenous or exogenous survival pathways, those exploiting the holotoxin should be left unscathed. Cell Death and Differentiation (2000) 7, 785 ± 794.

Burkitt lymphoma (BL) cells retain a high inherent propensity to undergo apoptosis indicating that net growth of the tumour population in vivo is likely to be influenced profoundly by its micro-environment. Here we investigate micro-environmental factors that affect BL-cell survival in vitro. We show that survival, and consequently net production, of tumour cells is enhanced by autocrine factors and, to a greater extent, by paracrine factors provided by relevant stromal elements of the tumour (fibroblasts and follicular dendritic cells) and by macrophages. Promotion of BL-cell survival by paracrine elements was mediated by cell/cell contact and by short-range soluble factor(s). IL-4, IL-10 and TNF-a promoted, whereas TGF-b1 inhibited, tumour-cell production. Macrophages engaged in phagocytosis of apoptotic BL cells were less effective than untreated macrophages in supporting net expansion of BL populations. These results suggest that the net production of tumour cells in BL is supported by multiple micro-environmental factors that modulate apoptosis. Cell Death and Differentiation (2000) 7, 59 ± 69.