急性髓系白血病（AML）异质性强，发病机制非常复杂，迄今未完全明了。前期研究表明SOX6低表达于AML细胞及CD34+AML干细胞中；SOX6过表达抑制了AML细胞系THP1增殖，阻滞了细胞周期；此外，我们借助逆转录病毒系统和小鼠移植模型，证实了SOX6过表达可显著延长AML小鼠的生存期。基于此，我们推测SOX6可能抑制AML发生发展，但其机制尚不清楚。本课题拟构建条件性过表达SOX6的基因敲入小鼠模型，并通过骨髓移植、血液免疫表型分析、骨髓病理学分析等方法进一步明确SOX6抑制AML发生发展的表型。借助CO-IP及质谱技术鉴定SOX6抑制AML的相关核内结合蛋白。结合RNA-seq、CHIP-seq及生物信息学解析SOX6的调控通路，并通过表达调控技术对候选效应分子进行功能验证。该课题将在AML动物模型上揭示SOX6抑制AML发生发展的分子机制，为AML临床靶向治疗提供理论依据。

Acute myeloid leukemia (AML) is a heterogeneous disease with variable clinical outcomes. The pathogenesis is very complex and so far the mechanism of AML remains elusive. Our preliminary results showed that the expression of SOX6 significantly decreased in AML cells and CD34+ AML stem cells, and that overexpression of SOX6 in THP1 cells inhibited cell proliferation, induced cell cycle arrest. It was confirmed that overexpression of SOX6 significantly extended the survival of AML mice with retroviral overexpression system in combination with mouse transplantation model. In order to study the mechanism for inhibition of the development of AML by SOX6, we propose to build an SOX6 conditional knockin mouse model. We will further dissect the phenotypes of sox6 inhibiting the develomment of AML by approaches including bone marrow transplantation, blood immunophenotyic analysis, as well as pathologic analysis. CO-IP and mass spectrometry will be performed to identify the binding protein of SOX6. RNA-seq, CHIP-seq and bioinformatics analysis will be performed to investigate the regulatory pathways of SOX6. Key candidate effectors correlating to SOX6 will be functionally evaluated by gene overexpression/knockdown approaches. This study will provide important insight into the mechanism and targeted treatment of AML.