Aurora-A经由p53/Mcl-1通路调控白血病干细胞自我更新的机制研究

白血病干细胞（Leukemia Stem Cell，LSCs）是白血病发生、发展和复发的根源。申请者完成日本学术振兴会资助项目时发现：基因沉默Aurora-A能够抑制LSCs的自我更新能力。 然而，Aurora-A调控该细胞自我更新能力的分子机制尚不清楚。前期研究发现：阻断 Aurora-A能够下调p53磷酸化。 进一步研究发现：基因沉默p53能够上调LSCs 中Mcl-1的表达，同时明显减弱Aurora-A抑制剂对该细胞自我更新能力的影响。此外，当LSCs转染外源性Mcl-1后，阻断Aurora-A并未明显抑制该细胞的自我更新能力。据此申请人提出以下科学假说：Aurora-A通过磷酸化作用下调p53功能活性，从而增强Mcl-1的表达，进而促进LSCs的自我更新能力。本项目的开展能够为研究白血病的发生发展机理、探寻临床更有针对性的治疗方法提供了新的思路。

Leukemia Stem cells (LSCs) are the root of leukemia development and relapse. We previously showed blockade of Aurora-A by a short hairpin (sh)RNA against Aurora-A significantly impaired self-renewal capability of LSCs, however, the mechanisms by which Aurora-A regulated the self-renewal capability of LSCs were unclear. Our recent results showed that down-regulation of Aurora-A by a shRNA potently decreased the phosphorylated forms of p53. In further study we found that silencing of p53 by a shRNA up-regulated the expression of Mcl-1 and attenuated the ability of MLN8237, a selective inhibitor of Aurora-A, to inhibit self-renewal capability of LSCs. Importantly, blockade of Aurora-A did not significantly impair self-renewal capability of LSCs when Mcl-1 was forced expressed in those cells. On the basis of these findings, we proposed the hypothesis that Aurora-A inhibited the activity of p53 via phosphorylation, which up-regulated the expression of Mcl-1 and enhanced the capacity of self-renewal of LSCs. This project will provide theoretical and experimental evidence for the development mechanism of leukemia and targeted clinical treatment.