蛋白激酶B
癌症研究
髓系白血病
造血
PI3K/AKT/mTOR通路
祖细胞
川地34
干细胞
生物
磷酸化
信号转导
细胞生物学
作者
Jing Yang,Takayuki Ikezoe,Chie Nishioka,Keiko Udaka,Akihito Yokoyama
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.
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