title: CD40 ligand, Bcl-2, and Bcl-xL spare group I Burkitt lymphoma cells from CD77-directed killing via Verotoxin-1 B chain but fail to protect against the holotoxin.
abstract: 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-xL 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.
authors.affiliation: MRC Centre for Immune Regulation, The University of Birmingham, Birmingham, UK. j.gordon@bham.ac.uk
authors.forename: J
authors.initials: J
authors.lastname: Gordon
authors.forename: A
authors.initials: A
authors.lastname: Challa
authors.forename: J M
authors.initials: JM
authors.lastname: Levens
authors.forename: C D
authors.initials: CD
authors.lastname: Gregory
authors.forename: J M
authors.initials: JM
authors.lastname: Williams
authors.forename: R J
authors.initials: RJ
authors.lastname: Armitage
authors.forename: J P
authors.initials: JP
authors.lastname: Cook
authors.forename: L M
authors.initials: LM
authors.lastname: Roberts
authors.forename: J M
authors.initials: JM
authors.lastname: Lord
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002051:Burkitt Lymphoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D023201:CD40 Ligand / Q000378:metabolism* / Q000494:pharmacology; D016923:Cell Death; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D022622:Shiga Toxin 1 / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D014281:Trihexosylceramides / Q000378:metabolism*; D051020:bcl-X Protein
chemical_list: D000911:Antibodies, Monoclonal; C494811:BCL2L1 protein, human; D021122:Protein Subunits; D019253:Proto-Oncogene Proteins c-bcl-2; D011956:Receptors, Cell Surface; D022622:Shiga Toxin 1; D014281:Trihexosylceramides; D051020:bcl-X Protein; D023201:CD40 Ligand; D015759:Ionomycin; C018549:globotriaosylceramide; D004247:DNA