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 fac tor-independent survival and a reduced susceptibility to apoptosis. Further more, Bcr-Abl kinase alters adhesion features by phosphorylating cytoskelet al and/or signaling proteins important for Integrin function. Integrin-medi ated adhesion to extracellular matrix molecules Is critical for the regulat ion of growth and apoptosis. However, effects of Integrin signaling on regu lation of apoptosis In cells expressing Bcr-Abl are largely unknown. The in fluence 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 wit h the same cells grown on laminin, on polylysin, or in suspension. Both inh ibition of Bcr-Abl kinase by ST1571 and Inhibition of specific adhesion rev ersed the fibronectin-mediated antiapoptotic effect In BaF3p185. The DNA da mage response of Bcr-Abl- BaF3 cells was not affected by adhesion to fibron ectin. In contrast to parental BaF3 cells, BaF3p185 adherent to fibronectin did not release cytochrome c to the cytosol following Irradiation. The fib ronectin-mediated antiapoptotic mechanism In Bcr-Abl-active cells was not m ediated by overexpression of Bcl-X-L or Bcl-2 but required an active phosph atidylinositol 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.