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

Academic Article

Abstract

  • 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.
  • Published In

  • Oncogene  Journal
  • Author List

  • Nishii K; Kabarowski JHS; Gibbons DL; Griffiths SD; Titley I; Wiedemann LM; Greaves MF
  • Start Page

  • 2225
  • End Page

  • 2234
  • Volume

  • 13
  • Issue

  • 10