The development of targeted therapies using FKHRL1 for the treatment of leukemia

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FKHRL1 (also called FOXO3a) is a member of the FOXO subfamily of Forkhead transcription factors and lies downstream of cytokine signaling pathways. This molecule is phosphorylated by activated Akt/Gsk and remains in the cytoplasm as an "inactive form". In this study, we found that FKHRL1 functions downstream of Bcr-Abl tyrosine kinase as a phosphorylated "inactive" form in chronic myelogenous leukemia (CML). The Bcr-Abl tyrosine kinase inhibitor imatinib induced cell cycle arrest and subsequent apoptosis via the conversion of FKHRL1 from the phosphorylated "inactive" form to the dephosphorylated "active" form in CML-derived cell lines. To examine whether "active" FKHRL1 can overcome the resistance to imatinib, we generated a 4-hydroxytamoxifen (4-OHT)-inducible "active" FKHRL1 (FKHRL1-TM ; a triple mutant of FKHRL1 in which all three Akt phosphorylation sites have been mutated)-estrogen receptor fusion protein expression system in CML-derived imatinib-resistant cell lines. 4-OHT inhibited the cell growth and cell cycle progression, and subsequently induced apoptosis, accompanied by up-regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Thus, "active" FKHRL1 antagonized deregulated proliferation and induced apoptosis in these cell lines.Moreover, we also found that all-trans retinoic acid (ATRA) induced apoptosis via FKHRL1-mediated TRAIL production in APL-derived cell line NB4 which was sensitive to ATRA. Like CML cells, over-expression of "active" FKHRL1 induced apoptosis not only in ATRA-sensitive cell line NB4 but also in ATRA-resistant NB4R cell line. Therefore, our results suggest that "active" FKHRL1 can overcome imatinib resistance and ATRA resistance in CML and APL cell lines, respectively, in part via TRAIL production.