BCR-ABL-MEDIATED RESISTANCE TO APOPTOSIS IS INDEPENDENT OF PI 3-KINASE ACTIVITY

The Bcr-Abl tyrosine kinase is responsible for the oncogenic phenotype observed in Philadelphia chromosome-positive leukemia and induces res istance to apoptotic cell death in a variety of cell types. Recent evi dence supports the hypothesis that these two properties of Bcr-Abl are derived from cooperative but distinct signaling pathways. Phosphatidy linositol 3-kinase (Pl3K), which has been suggested to associate with and become activated by Bcr-Abl, has been shown to be required for Bcr -Abl-mediated cell growth, Also, Pl3K has been implicated in resistanc e to apoptosis induced by some growth factors. We therefore examined t he role of Pl3-kinase in the anti-apoptotic effect of Bcr-Abl, First, we confirmed that expression of p185(bcr-abl) in HL-60 cells, which re nders these cells resistant to apoptosis, induces tyrosine phosphoryla tion of the p85 subunit of Pl3K. Consistent with this result, we obser ved a 20-fold increase in Pl3K activity upon immunoprecipitation of ty rosinephosphorylated proteins from cells expressing Bcr-Abl versus con trol cells. Nevertheless, treatment of HL-60.p185(bcr-abl) cells with wortmannin, a potent inhibitor of PI3K, eliminated Pl3K activity but d id not interfere with the resistance of these cells to apoptosis. Simi lar results were obtained with the CML line K562 and with the BaF3.p18 5 (bcr-abl) line. We conclude that while Pl3K participates in the anti -apoptotic response mediated by some growth factors and also seems to be important for the growth of Bcr-Abl-positive cells, it does not pla y any role in Bcr-Abl-mediated resistance to apoptosis.