Bcr-Abl activates AURKA and AURKB in chronic myeloid leukemia cells via AKT signaling

摘要

This study explored molecular mechanisms by which Bcr-Abl induced expression of Aurora kinase A and B (AURKA and AURKB) in chronic myeloid leukemia cells. Lentiviral transduction of Bcr-Abl into either Ba/F3 or CD34+ hematopoietic stem/progenitor cells potently increased levels of AURKA and AURKB in association with phosphorylation of AKT and stimulated their proliferation. Bcr-Abl-mediated expression of AURKA and AURKB were decreased in CD34+ HSPCs when AKT was inactivated by an shRNA against AKT, suggesting that Bcr-Abl induced expression of AURKA and AURKB via AKT signaling. MLN8237, an inhibitor of AURKA, significantly inhibited the proliferation of freshly isolated CD34+ CML cells in a dose-dependent manner as measured by colony forming assay. Importantly, inhibition of AURKA in CD34+ leukemia cells freshly isolated from individuals with blast crisis of CML with Bcr-Abl T315I mutant (n = 2) by MLN8237 significantly impaired the engraftment of these cells in severely immunocompromised mice and decreased the weight of spleens. Taken together, Bcr-Abl induces expression of AURKA and AURKB at least in part via AKT. Inhibition of AURKA could be useful to overcome imatinib-resistance mediated by Bcr-Abl mutants.