Differential regulation of the p70 S6 kinase pathway by interferon {alpha} and imatinib mesylate (STI571) in chronic myelogenous leukemia cells.

The precise mechanisms by which imatinib mesylate and IFNalpha exhibit antileukemic effects are not known. We examined the effects of IFNs or imatinib mesylate on signaling pathways regulating initiation of mRNA translation in BCR-ABL expressing cells. Treatment of IFN sensitive KT-1 cells with IFNalpha resulted in phosphorylation/activation of mTOR and downstream activation of p70S6K. The IFN activated p70S6K was found to regulate phosphorylation of S6 ribosomal protein, which regulates translation of mRNAs with oligopyrimidine tracts in the 5′-untranslated region. In addition, IFNalpha -treatment resulted in an mTOR- and/or PI3′kinase-dependent phosphorylation of 4E-BP1 repressor of mRNA translation on sites that are required for its de-activation and dissociation from the eIF4E-complex. In contrast to the effects of IFNs, STI571 suppressed p70 S6K activity, consistent with inhibition of BCR-ABL mediated activation of the mTOR/p70S6K pathway. Moreover, the mTOR inhibitor rapamycin enhanced the suppressive effects of STI571 on primary leukemic CFU-GM progenitors from CML-patients. Taken altogether, our data demonstrate that IFNs and STI571 differentially regulate PI3′-kinase/mTOR-dependent signaling cascades in BCR-ABL-transformed cells, consistent with distinct effects of these agents on pathways regulating mRNA translation. They also support the concept that combined use of STI571 with mTOR inhibitors may be an appropriate future therapeutic strategy for the treatment of CML.