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Bax Is Frequently Compromised in Burkitt’s Lymphomas with Irreversible Resistance to Fas-induced Apoptosis

Lymphoma Biology Section, Pediatric Oncology Branch, National Cancer Institute, NIH [M. I. G., A. H., I. M., K. B.], and Division of Hematological Products, Center for Biological Evaluation and Research [B. C., G. T., H. M.], Food and Drug Administration, Bethesda, Maryland 20892

We have analyzed the Fas-mediated death pathway in a panel of 11 Epstein-Barr virus (EBV)-negative and 10 EBV-positive Burkitt’s lymphoma (BL) cell lines. We show that the increased expression of Fas in EBV-positive cell lines is mediated via LMP-1. Four of the 21 BL cell lines are readily responsive to Fas-mediated cell death signals. Of the remaining 17 cell lines, 10 can be sensitized by up-regulating Fas either via exogenous expression of LMP-1 or via treatment with CD40L. These same cell lines can also be sensitized by treatment with cycloheximide (CHX), which, however, does not result in up-regulation of Fas. Neither up-regulation of Fas, nor treatment with CHX, restore Fas sensitivity in seven BL cell lines. Further analyses indicated that 5 of the 7 cell lines (and none of the 14 responsive cell lines) were also compromised in the integrity/expression of the proapoptotic gene Bax. Thus, in most BL cell lines, the Fas pathway seems to be inhibited, although the mechanism of inhibition varies. The correlation between Bax mutation and irreversible (by CD40L or CHX) Fas resistance raises the possibility, for the first time, that Bax may play a critical function in Fas-mediated cell death in BL.

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