Abstract
3375
STI-571 (imatinib mesylate, Gleevec trade mark) is an ATP analogue that competitively binds to and inhibits the BCR-ABL tyrosine kinase, resulted from the chromosomal translocation t(9; 22) in chronic myelogenous leukemia (CML) cells. CML cells are highly resistant to apoptosis induced by conventional chemotherapeutic drugs. Survival signals triggered by the BCR-ABL oncogene have been addressed and a number of signal transducers and transcription factors have been associated with the antiapoptotic phenotype of CML cells, some of which lead to the expression and/or activation of members of the Bcl-2 family of apoptosis modulators, such as Bcl-xL and Bad. By using quantitative real time reverse transcription-polymerase chain reaction (RT-PCR) and western blot analysis, in this study we measured expression levels of the IAP protein survivin in two CML cell lines (STI-571- sensitive and -resistant K562 and LAMA-84, respectively) as well as in freshly isolated bone marrow cells from CML patients treated with STI-571. We also investigated Survivin expression in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) TOM-1 cells. We show here that STI-571 specifically inhibits, in a dose dependent manner, survivin expression in Ph+ CML and ALL cells whereas does not in Ph- U937 cells. Moreover, we demonstrated that STI-571-induced apoptosis in K562 cells is correlated with the down-regulation of survivin expression. These findings suggest that BCR-ABL oncogene regulate survivin expression in Ph+ cells.
- American Association for Cancer Research