ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block

Using a temperature-sensitive mutant of the p210 BCR-ABL gene, transfected into a growth factor-dependent cell line (BaF3), we show that transient BCR-ABL kinase expression increases single cell and clonogenic resistance to apoptosis arising from genotoxic damage induced by ionizing radiation and VP...

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Bibliographic Details
Published in:	Oncogene Vol. 13; no. 10; p. 2225
Main Authors:	Nishii, K, Kabarowski, J H, Gibbons, D L, Griffiths, S D, Titley, I, Wiedemann, L M, Greaves, M F
Format:	Journal Article
Language:	English
Published:	England 21-11-1996
Subjects:	Antineoplastic Agents, Phytogenic - pharmacology Apoptosis - drug effects Apoptosis - radiation effects bcl-2-Associated X Protein bcl-X Protein Caffeine - pharmacology Cell Line - drug effects Cell Line - radiation effects Enzyme Induction - drug effects Etoposide - pharmacology Fusion Proteins, bcr-abl - metabolism G1 Phase - drug effects G2 Phase - drug effects G2 Phase - radiation effects Interleukin-3 - pharmacology Mitosis - radiation effects Phosphodiesterase Inhibitors - pharmacology Phosphorylation Protein Kinases - metabolism Proto-Oncogene Proteins - metabolism Proto-Oncogene Proteins c-bcl-2 - metabolism Radiation Tolerance Temperature
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Summary:	Using a temperature-sensitive mutant of the p210 BCR-ABL gene, transfected into a growth factor-dependent cell line (BaF3), we show that transient BCR-ABL kinase expression increases single cell and clonogenic resistance to apoptosis arising from genotoxic damage induced by ionizing radiation and VP-16/etoposide. This effect is achieved in the absence of any detectable changes in the levels of BCL-2, BAX or BCL-x proteins and is independent of proliferative, MAP kinase-dependent effects of BCR-ABL kinase. In contrast to parental cells that transiently arrest in G2 and then apoptose, p210 BaF3 cells show a pronounced and sustained G2 arrest following radiation coupled with enhanced phosphorylation of cdc2. A cell cycle block in early M phase induced by the mitotic spindle poison, nocodazole, does not provide protection from apoptosis. Reversal of G2 arrest by caffeine abolishes the protective effect of BCR-ABL kinase. These data provide further insight into the transforming properties of BCR-ABL and are relevant to the clinical intransigence of Ph-positive leukaemias.
ISSN:	0950-9232