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

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.

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