TET2早期突变形成的克隆性造血是目前慢性粒单核细胞白血病（CMML）发病模型中重要的驱动因素。前期研究表明TET2的酶催化活性和转录调控功能是可分离的，TET2 N端的错义突变对转录和5mC催化活性都有影响。为更好模拟TET2突变在人体的致病过程，本研究将选取CMML中TET2的2个热点突变：Q916*和R1516*，构建造血系统特异性Tet2点突变小鼠模型，通过表型鉴定、甲基化测序、RNA测序、qPCR、Western blot、免疫荧光等体内外实验探索Tet2 Q916*及R1516*突变对CMML发病的作用和机制。然后检测突变小鼠对低甲基化药物（HMA）治疗的反应率，并根据突变结构域功能选择合适治疗靶点，探索HMA联合用药方案。本课题对深入探索TET2不同结构域突变对CMML的致病作用，预测HMA治疗反应及探索联合用药方案有重要意义。

Clonal hematopoiesis with TET2 early mutation is an important driving factor in the current pathogenesis model of chronic myelomonocytic leukemia (CMML). Our previous studies have shown that the catalytic and transcriptional functions of TET2 are separable and that missense mutations outside of the catalytic domain negatively impact TET2’s activity. To better simulate the pathogenic process of TET2 mutations in CMML, our study proposes to select the hotpoint mutations of TET2 in CMML-Q916* and R1516*, and construct hematopoietic specific Tet2 mutant mouse models. We will explore the role and mechanism of Tet2 Q916* and R1516* mutations in the pathogenesis of CMML through in vivo and in vitro experiments, such as methylation sequencing, RNA sequencing, qPCR, western blot and Immunofluorescence. Then we will detect the response of mutant mice treating with hypomethylating agents (HMA), and explore the appropriate combined drug regimen depending on the function of the mutant domain. This study may bring great significance on reveling the pathogenic effect of TET2 mutations in CMML, predicting the therapeutic response of HMA and exploring the combined treatments with HMA in CMML.