PTEN通过AKT和BMI1调控造血干细胞的分子和遗传机制

Hematopoietic system constantly produces new mature progeny and maintain human health. PTEN is a negative regulator of PI3K-AKT signaling and is involved in the regulation of hematopoietic stem cells (HSCs) and system. We and others has reported that PTEN loss in murine HSCs results in abnormal hematopoietic differentiation and acute T lymphoblastic leukemia. We have also observed that Pten deletion does not appear to interfere with HSC self-renewal, which is inconsistent with the previous reports. This discrepancy may be associated with lack of AKT phosphorylation in the HSCs of our model. Furthermore, we have observed that both the homozygous deletion of Pten and heterozygous deletion of Bmi1 result in rapid loss of adult HSCs. Based on our previous results, we propose to study the novel AKT-dependent and independent regulation of HSC: (1) The double knockout mice of Pten and Ship, Encoding two negative regulators of AKT, will be generated to study the role of activated AKT in HSCs; (2) the mice with the homozygous deletion of Pten and heterozygous deletion of Bmi1 (Bmi1-GFP) will be used to understand the axis of PTEN-BMI1 in HSC regulation. (3) The AKT-dependent and -independent regulatory network in HSCs will be studied through RNAseq and bioinformatic analysis.

造血系统不断自我更新和分化出新成熟血细胞，维持机体正常功能。PTEN是PI3K-AKT信号通路的负调控因子，在造血干细胞（HSC）和造血系统中有重要的调控功能。我们和他人前期发现，在小鼠HSC中敲除Pten会导致造血系统分化异常，进而导致急性T细胞白血病。但我们发现Pten敲除不会导致HSC自我更新丧失，与以前报道不同，这可能由于在HSC中Pten敲除没有激活下游激酶AKT。同时我们还发现PTEN能与BMI1在HSC中协同调控HSC。所以，我们申请研究在HSC中新颖的AKT依赖性和AKT非依赖性（PTEN-BMI1）的不同调控功能：（1）建立HSC中双敲除两个AKT负调控因子Pten和Ship的小鼠模型，从而研究激活的AKT对HSC功能的影响；（2）利用Pten敲除和Bmi1单拷贝敲除的小鼠研究PTEN-BMI1的协同调控HSC机制；（3）研究PTEN调控HSC的两种方式的转录调控网络。