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The Suppression of Drug-induced Apoptosis by Activation of v-ABL Protein Tyrosine Kinase¹

Leukaemia Research Fund Group, Department of Biochemistry, University of Manchester Institute of Science and Technology, Manchester M60 1QD, United Kingdom [A. D. W.] and The Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, Stopford Building (G38), University of Manchester, Manchester M13 9PT, United Kingdom [R. S. C., C. D.]

Cells with a temperature-sensitive mutant of the v-abl oncoprotein (IC.DP) were treated with the anticancer drugs melphalan or hydroxyurea. At the restrictive temperature for v-ABL protein tyrosine kinase activity, drug-treated IC.DP cells died by apoptosis. In contrast, apoptotic cell death induced by either drug was suppressed when v-ABL was active. However, melphalan-induced accumulation of cells in the S and G₂-M phases of the cell cycle was unaffected by v-ABL activation. Moreover, the continuous presence of v-ABL activity was necessary to suppress apoptosis. This suggested that melphalan had interacted with DNA and that v-ABL activity prevented the coupling of drug-induced damage to the apoptotic pathway. IC.DP cells exhibited similar levels and subcellular localization of the BCL-2 protein irrespective of v-ABL activation status, thus v-ABL-mediated cell survival appeared to be independent of BCL-2.

¹ This work was supported by a grant to C. D. and A. D. W. from the United Kingdom Leukaemia Research Fund. C. D. is a United Kingdom Cancer Research Campaign Senior Fellow.

² To whom requests for reprints should be addressed.

Received 3/ 2/94. Accepted 7/26/94.

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