BCR/ABL Regulation of PI-3 Kinase Activity

The ability of BCR-ABL oncoproteins to induce leukemic transformation of hematopoietic cells depends on their tyrosine kinase activity, which is essential for recruitment and activation of multiple pathways that transduce oncogenic signals. Although it is unknown yet whether activation of PI 3-kinase is required for transformation, the colony-forming ability of Philadelphia1 cells is dependent on PI 3-kinase activity, as indicated by the results of studies using a number of strategies to interfere with the synthesis and/or the function of the regulatory and catalytic subunits of this kinase. In particular, wortmannin, a specific PI 3-kinase inhibitor, preferentially affected colony formation of Philadelphia1 cells over that of normal marrow hematopoietic progenitors. The mechanism(s) of such effects are unknown, but PI 3-kinase inhibitors may represent a novel class of therapeutic agents for the ex vivo and/or in vivo treatment of Philadelphia1 leukemias.