Department of Hematology and Respiratory Medicine, Kochi University, Nankoku, Kochi, Japan; Department of Immunology, Kochi Medical School, Kochi University, Kochi University, Nankoku, Kochi, Japan.
Int J Cancer. 2014 Mar 1;134(5):1183-94. doi: 10.1002/ijc.28434. Epub 2013 Sep 3.
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.
本研究探讨了 Bcr-Abl 诱导慢性髓系白血病细胞中 Aurora 激酶 A 和 B（AURKA 和 AURKB）表达的分子机制。慢病毒转导 Bcr-Abl 进入 Ba/F3 或 CD34(+)造血干/祖细胞中，可显著增加 AURKA 和 AURKB 的水平，与 AKT 的磷酸化相关，并刺激其增殖。当 AKT 被 AKT 的 shRNA 失活时，Bcr-Abl 介导的 AURKA 和 AURKB 在 CD34(+)HSPCs 中的表达减少，这表明 Bcr-Abl 通过 AKT 信号诱导 AURKA 和 AURKB 的表达。AURKA 的抑制剂 MLN8237 通过集落形成测定法以剂量依赖性方式显著抑制新鲜分离的 CD34(+)CML 细胞的增殖。重要的是，用 MLN8237 抑制 Bcr-Abl T315I 突变体（n = 2）个体中新鲜分离的 CD34(+)白血病细胞中的 AURKA，可显著损害这些细胞在严重免疫缺陷小鼠中的植入，并减少脾脏重量。总之，Bcr-Abl 通过 AKT 至少部分诱导 AURKA 和 AURKB 的表达。抑制 AURKA 可能有助于克服 Bcr-Abl 突变体介导的伊马替尼耐药性。
