CD40 ligand, Bcl-2, and Bcl-x(L) spare group I Burkitt lymphoma cells fromCD77-directed killing via Verotoxin-1 B chain but fail to protect against the holotoxin

Owing to its lineage and differentiation stage-restricted expression, CD77 has been mooted as a therapeutic target in Burkitt lymphoma (BL). The recog nition that the globotriaosyl moiety of this neutral glycosphingolipid is a receptor for Escherichia coli derived Verotoxin-1 (Shiga-Like Toxin-1) off ers a potential delivery system for the attack, Here we show that CD77-expr essing Group I BL cells which are normally susceptible to activation-induce d death on binding Verotoxin-1 B chain are protected in the presence of CD4 0 ligand, Ectopic expression of either bcl-2 or bcl-x(L) also afforded resi stance to the actions of the B chain. In total contrast, neither of the sur vival genes nor a CD40 signal - even when acting in concert - protected aga inst killing mediated by the holotoxin. These findings indicate that while therapeutic modalities for CD77-expressing B cell tumors (which include fol licular lymphoma) based on the use of Verotoxin-1 B chain might be compromi sed by the activation of endogenous or exogenous survival pathways, those e xploiting the holotoxin should be left unscathed.