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E1A Overcomes the Apoptosis Block in BCR-ABL+ Leukemia Cells and Renders Cells Susceptible to Induction of Apoptosis by Chemotherapeutic Agents¹

Institute of Molecular Biology (Cancer Research) [T. S., K. P., H. E., B. M. P.] and Department of Internal Medicine, West German Cancer Center [B. O.], University of Essen Medical School, Hufelandstrasse 55, D-45122 Essen, Germany

A crucial function of the BCR-ABL chimeric gene in chronic myeloid leukemia is the prolongation of cell survival by inhibition of apoptosis. BCR-ABL expression confers cross-resistance to multiple genotoxic anticancer drugs by inhibition of the apoptotic response to DNA damage in association with cell cycle arrest at the G₂-M restriction point. Previous reports indicated that BCR-ABL exerts its antiapoptotic effect against various apoptotic stimuli upstream to the cleavage and activity of caspase-3. Here we show that the adenovirus E1A protein induces substantial apoptosis in BCR-ABL expressing K562 and LAMA-84 leukemia cells. This apoptotic activity of E1A is accompanied by processing of caspase-3 and cleavage of poly(ADP-ribose) polymerase and can be significantly blocked by z-VAD-fmk Z-Val-Ala-Asp(OCH₃)-CH₂F and the caspase-3-specific inhibitor Z-DEVD-FMK Z-Asp(OCH₃)-Glu-Val-Asp(OCH₃)-CH₂F. Moreover, E1A renders K562 cells, which are particularly resistant to cell death irrespective of the inducing agent, susceptible to induction of apoptosis by the chemotherapeutic agents etoposide and daunorubicin. Counteracting the DNA damage-induced inactivation of cdc2 kinase, E1A reverses the drug-induced G₂-M arrest. These results indicate that solitary delivery of E1A significantly antagonizes BCR-ABL-induced antiapoptotic functions and circumvents the inherent resistance to DNA damage-induced apoptosis, supporting the use of E1A in combination with chemotherapeutic agents as a promising therapeutic strategy for successful treatment of Philadelphia chromosome-positive leukemia in vivo.

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