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bcl-2 Gene Transfer Increases Relative Resistance of S49.1 and WEHI7.2 Lymphoid Cells to Cell Death and DNA Fragmentation Induced by Glucocorticoids and Multiple Chemotherapeutic Drugs¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6082

The S49.1 and WEHI7.2 murine lymphoid cell lines have been used extensively as models for investigations of programmed cell death ("apoptosis") induced by glucocorticoids such as dexamethasone. Infection of these thymus-derived T-cell lines with a recombinant retrovirus encoding the human M_r 26,000 Bcl-2 oncoprotein resulted in marked resistance to DEX-mediated cell death and DNA degradation into oligonucleosomal fragments, without interfering with the ability of dexamethasone to suppress cellular proliferation and without lowering levels of glucocorticoid receptors. In contrast, high levels of p26-Bcl-2 production did not block cell killing and DNA fragmentation induced by H₂O₂, suggesting that the Bcl-2 impairs some but not all pathways for cell death in S49.1 and WEHI7.2 cells that are associated with the DNA fragmentation pattern typical of apoptosis. S49.1 and WEHI7.2 cells infected with bcl-2 but not control retrovirus also exhibited increased resistance to cell killing and DNA fragmentation induced by a wide variety of reagents, including the calcium ionophore ionomycin, the phorbol ester tetradecanoylphorbol acetate, the dihydrofolate reductase inhibitor methotrexate, the antimetabolite 1-ß-D-arabinofuranosylcytosine, and the microtubule inhibitor vincristine. These findings provide evidence that p26-Bcl-2 interferes with a pathway for cell death that is activated by multiple drugs used for the treatment of cancer.

¹ This work was supported by NIH Grant CA-47956.

² Scholar of the Leukemia Society of America. To whom requests for reprints should be addressed, at La Jolla Cancer Research Foundation, Cancer Research Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037.

Received 7/ 8/92. Accepted 8/19/92.

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