SELECTIVE INDUCTION OF APOPTOSIS IN PHILADELPHIA-CHROMOSOME-POSITIVE CHRONIC MYELOGENOUS LEUKEMIA-CELLS BY AN INHIBITOR OF BCR-ABL TYROSINEKINASE, CGP-57148

The BCR-ABL tyrosine kinase has been implicated as the cause of Philad elphia chromosome (Ph-1)-positive leukemias, We report herein that CGP 57148, a selective inhibitor of the ABL tyrosine kinase, caused apopt osis specifically in bcr-abl-positive chronic myelogenous leukemia (CM L) cells; K562 and KYO-1, Upon treatment with CGP 57148, CRKL, a speci fic substrate for BCR-ABL that propagates signals via phosphatidylinos itol-3' kinase (PI3K), was dephosphorylated, indicating inhibition of BCR-ABL tyrosine kinase at the cellular level. Likewise, MAPK/ERK, a d ownstream mediator of Ras, was also dephosphorylated. Caspase activati on and cleavage of retinoblastoma protein (QRB) accompanied the develo pment of CGP 57148-induced apoptosis. Inhibition of caspase suppressed apoptosis and the cleavage of pRB, and in turn arrested cells in the 81 phase. These results indicate that CGP 57148 shows apoptogenic and anti-proliferative effects on bcr-abl-positive cells by blocking BCR-A BL-initiated signaling pathways.