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Medline ® Abstract for Reference 191

of 'Cellular and molecular biology of chronic myeloid leukemia'

191
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ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block.
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Nishii K, Kabarowski JH, Gibbons DL, Griffiths SD, Titley I, Wiedemann LM, Greaves MF
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Oncogene. 1996;13(10):2225.
 
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.
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Leukaemia Research Fund Centre, Institute of Cancer Research, London, UK.
PMID