APOPTOSIS OF BURKITTS-LYMPHOMA CELLS INDUCED BY SPECIFIC INTERACTION OF SURFACE IGM WITH A SELF-ANTIGEN - IMPLICATIONS FOR LYMPHOMAGENESIS IN ACQUIRED-IMMUNODEFICIENCY-SYNDROME

In a previous study, we described a cell line (BRG-P) derived from a w oman with Burkitt's lymphoma (BL) and acquired immunodeficiency syndro me that shared the same characteristic cytogenetic abnormalities as th e patient's malignant cells. This cell line contained subclones that d isplayed an isotype switch from IgM to IgA1 and an accumulation of poi nt mutations in the V-H region genes. Because these two features sugge sted an antigen-driven process, we began a search for the antigen resp onsible for the stimulation of the malignant B cells. Specifically, we hypothesized that, because the patient's tumor had presented as a lym phomatous infiltration of the breast, the malignant B cells were recru ited to this site because of the reactivity of their surface lg with b reast tissue. A hybridoma (BRG-H) was obtained by fusing BRG-M cells ( an IgM producing subclone of the BRG-P cell) with an appropriate cellu lar partner. The monoclonal antibody (BRG MoAb) produced by this hybri doma reacted strongly with two of five breast cancer cell lines and st ained normal and malignant ductal epithelial cells on breast tissue se ctions. The antigen recognized by the BRG MoAb consisted of a single, minimally glycosylated polypeptide chain of 45 kD (p45). The BRG MoAb failed to react with a panel of human cell lines from different tissue s, except for one cell line from a uterine cervical carcinoma. No reac tivity was detected for a panel of exogenous antigens from various pat hogens, including human immunodeficiency virus and self-antigens frequ ently recognized by polyspecific antibodies. Experiments were performe d to investigate the functional consequences of the interaction of sur face IgM with its specific ligand. Coculture of BRG-M cells with p45(), but not with p45(-), breast cells caused apoptosis of BRG-M cells. The specificity of the interaction was shown by the observation that a poptosis was prevented by pretreatment of BRG-M cells with a monovalen t F(ab') fragment of rabbit IgG antibody to human mu chains. Moreover, only BRG-M cells, but not other BL cells, underwent apoptosis after e xposure to p45(+) breast cells. The interaction between the CD40 molec ule expressed by BRG-M cells and its specific ligand (CD40L) prevented p45-induced cell apoptosis. Because this interaction mimics that occu rring in vivo between T and B cells during immune responses, our data suggest that various events contributed to the emergence of the BL, in this particular patient, including antigenic stimulation possibly ass isted by T-cell help. (C) 1996 by The American Society of Hematology.