Notch信号通路参与多种肿瘤的发生发展，目前尚无Notch信号通路在幼年型粒单核细胞白血病（JMML）中功能的研究。我们前期研究发现，在癌基因KrasG12D诱导的JMML小鼠中下调Notch信号通路，可以显著缩短小鼠的生命周期并促使小鼠脾脏进一步增大，提示Notch信号通路参与了JMML的发生发展。本项目拟在前期研究的基础上, 通过将疾病小鼠的骨髓细胞移植到健康受体小鼠体内，分析受体小鼠疾病相关指征，利用流式细胞仪检测造血系统变化, 并利用RNA测序进行转录组学分析，从而可以研究下调Notch信号通路在JMML中的细胞自主性作用。同时，将健康小鼠的骨髓细胞移植到疾病小鼠体内，分析小鼠疾病相关指征，利用细胞因子芯片分析细胞因子表达，以研究Notch信号通路在JMML中的非细胞自主性作用。本项目将为JMML的致病机制提供新的线索，并为Notch信号通路在JMML中的临床应用提供理论依据。

Previous studies showed that Notch signaling can be either oncogenic or tumor suppressive during tumorigenesis. At present, there is no report about the role of Notch signaling in Juvenile myelomonocytic leukemia (JMML). Our preliminary data showed that downregulation of Notch signaling significantly promotes JMML development, including shortened survival and further enlarged spleen, in a KrasG12D induced JMML mouse model, which suggests that Notch signaling is involved in the development of JMML. To further investigate the underlying cellular mechanism, we will use bone marrow transplantation to study both cell-autonomous and non-cell-autonomous effects of Notch signaling in same JMML mouse model simultaneously. By transplanting bone marrow cells from JMML mice into wild type recipient mice, we can investigate the cell-autonomous effects of Notch signaling in JMML development. We will use RNA-seq to explore the gene expression after downregulation of Notch signaling. Meanwhile, bone marrow cells form wild type mice will be transplanted into JMML recipient mice by reciprocal transplantation. Then, we can study the non-cell-autonomous effect of Notch signaling in JMML development. Cytokine array will be used to study the changes of cytokines after downregulation of Notch signaling in the bone microenvironment. Our study will provide insight into the pathogenic and therapeutic roles of Notch signaling in JMML.