The tyrosine kinase inhibitor CGP 57148 (ST1 571) induces apoptosis in BCR-ABL-positive cells by down-regulating BCL-X

CGP 57148 is a potent inhibitor of the ABL protein tyrosine kinase and a pr omising new compound for the treatment of a variety of BCR-ABL-positive leu kemias, We used this enzyme inhibitor to characterize the biological effect s of BCR-ABL in primary cells and two growth factor-dependent BCR-ABL-trans fected cell lines. The effect of CGP 57148 on primary cells is dependent on the stage of diffe rentiation. The growth of maturing chronic myeloid leukemia cells is indepe ndent of BCR-ABL in the presence of growth factors. However, the proliferat ion of leukemic immature cobblestone-forming area cells is almost completel y blocked after the inhibition of the BCR-ABL kinase, In the BCR-ABL-transf ected cell lines, M07/p210 and Ba/F3/p185, CGP 57148 induces apoptosis by r eleasing cytochrome c, activating caspase 3, and cleavage of PARP. No alter ation of the expression level of the apoptosis regulator BCL-2 was observed . In contrast, BCL-X was down-regulated after exposure to CGP 57148, Inhibi tors of signal transduction proteins such as PI-3 kinase, mitogen-activated protein/extracellular signal-regulated kinase kinase, and Janus-activated kinase 2 pathways were not capable of a comparable down-regulation of BCL-X , The Fas/Fas ligand system was not involved either in the induction of apo ptosis by CGP 57148, We conclude that the inhibition of the BCR-ABL kinase by CGP 57148 (a) preferentially inhibits the growth of immature leukemic pr ecursor cells, (b) efficiently reverts the antiapoptotic effects of BCR-ABL by down-regulation of BCL-X, and (c) is more effective than the inhibition of the downstream signal transduction pathways of PI-3 kinase, mitogen-act ivated protein/extracellular signal-regulated kinase kinase, and Jams-activ ated kinase 2.