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, whic h is essential for recruitment and activation of multiple pathways tha t transduce oncogenic signals. Although it is unknown yet whether acti vation of PI 3-kinase is required for transformation, the colony-formi ng ability of Philadelphia(1) cells is dependent on PI 3-kinase activi ty, as indicated by the results of studies using a number of strategie s to interfere with the synthesis and/or the function of the regulator y and catalytic subunits of this kinase. In particular, wortmannin, a specific PI 3-kinase inhibitor, preferentially affected colony formati on of Philadelphia(1) cells over that of normal marrow hematopoietic p rogenitors. The mechanism(s) of such effects are unknown, but PI 3-kin ase inhibitors may represent a novel class of therapeutic agents for t he ex vivo and/or in vivo treatment of Philadelphia(1) leukemias.