Adhesion to fibronectin selectively protects Bcr-Abl+ cells from DNA damage-induced apoptosis

The phenotype of Bcr-Abl-transformed cells is characterized by a growth factor-independent survival and a reduced susceptibility to apoptosis. Furthermore, Bcr-Abl kinase alters adhesion features by phosphorylating cytoskeletal and/or signaling proteins important for Integrin function. Integrin-mediated adhesion to extracellular matrix molecules Is critical for the regulation of growth and apoptosis. However, effects of Integrin signaling on regulation of apoptosis In cells expressing Bcr-Abl are largely unknown. The influence of adhesion on survival and apoptosis In Bcr-Abl(+) and Bcr-Abl(-) BaF3 cells was Investigated. p185bcr-abl-transfected BaF3 cells preadhered to immobilized fibronectin had a significant survival advantage and reduced susceptibility to apoptosis following gamma -irradiation when compared with the same cells grown on laminin, on polylysin, or in suspension. Both inhibition of Bcr-Abl kinase by ST1571 and Inhibition of specific adhesion reversed the fibronectin-mediated antiapoptotic effect In BaF3p185. The DNA damage response of Bcr-Abl- BaF3 cells was not affected by adhesion to fibronectin. In contrast to parental BaF3 cells, BaF3p185 adherent to fibronectin did not release cytochrome c to the cytosol following Irradiation. The fibronectin-mediated antiapoptotic mechanism In Bcr-Abl-active cells was not mediated by overexpression of Bcl-X-L or Bcl-2 but required an active phosphatidylinositol 3-kinase (PI-3K). Kinase-active Bcr-Abl in combination with fibronectin-induced integrin signaling led to a hyperphosphorylation of AKT. Thus, cooperative activation of PI-3K/AKT by Bcr-Abl and integrins causes synergistic protection of Bcr-Abr cells from DNA damage-induced apoptosis. (C) 2001 by The American Society of Hematology.