蛋白激酶的靶向药物在白血病治疗中取得突破，但白血病干细胞(LSC)导致的耐药是制约疗效的瓶颈。我们研究表明细胞周期激酶AURKA在LSC中异常表达，靶向其激酶活性可抑制肿瘤细胞增殖(Blood 2008; Mol Cancer Res 2013)；新近发现其非激酶依赖功能可调控肿瘤干细胞的自我更新(Nat Commun 2016)。据此，我们提出靶向AURKA针对LSC的治疗新策略：通过靶向AURKA激酶及非激酶依赖“双活性点”，抑制髓系白血病细胞增殖及LSC的自我更新。我们运用原代细胞模型、BCR-ABL及MLL-ENL白血病小鼠模型，探究AURKA激酶活性及非激酶转录调控通路(AURKA-MYC/STAT5) 在LSC中自我更新机制，进而研发新型激酶抑制剂及非激酶依赖的分子靶向化合物以干预AURKA激酶及非激酶功能，探索“一靶双点”新型靶向模式，拓展以蛋白激酶为靶点的白血病治疗新策略。

Kinase-targeted drugs have achieved significant success in leukemia targeted therapy. However, the leukemia stem cell (LSC) has been the bottleneck of tumor treatment that limits the curative effect. Our previous studies have found that aberrant expression of cell cycle kinase Aurora A (AURKA) in LSC. Targeting the kinase activity of AURKA suppressed proliferation of leukemia cells (Blood 2008; Mol Cancer Res 2013); We recently found that the kinase-independent function of AURKA regulate self-renewal ability of cancer stem cell（Nat Commun 2016). Therefore, we put forward a new strategy of targeting AURKA against LSC, which is to inhibit the proliferation of myeloid leukemia cells and self-renewal ability of LSC by targeting the kinase and nonkinase activity of AURKA, termed "double activity points". We explore the kinase and nonkinase-dependent transcription pathway (AURKA - MYC/STAT5) that regulate self-renewal mechanism of AURKA, through the establishment of primary cell model, BCR - ABL and MLL - ENL leukemia mice model and clinical specimens.We will further design drugs targeting the kinase and nonkinasedependent function of AURKA, exploring the new model of "one target against two points ". Therefore, this project will expand a novel strategy in leukemia targeted therapy.