应用条件性MLL-AF6基因敲入小鼠研究DNA甲基化在MLL白血病发病中的作用

MLL leukemia is a distinct leukemia subtype which confers an extremely poor prognosis. Recent studies reported that epigenetic abnormalities play a key role in the leukemogenesis of MLL leukemia. Therefore, screening for genes or pathways regulated by epigenetic process presents the mainstream of targeting therapy in this research landscape. It has been reported that the transformation and maintenance of MLL leukemia may be driven by changes of DNA methylation pattern. However, the information of DNA methylation pattern must be "read" and "interpreted" by the MBD protein which will regulate gene expression, indicating MBD protein as a reasonable target in DNA methylation research. To identify the role of DNA methylation in the leukemogenesis of MLL leukemia, we will employ the existing conditional MLL-AF6 knock-in mice and MBD2 knock-out mice models in this study. Meanwhile, using bioinformatics analyses, the key genes regulated by DNA methylation will also be screened and validated in the mice models. This study will decode the epigenetic mechanism and provide novel therapeutic targets for MLL leukemia.

MLL白血病是一种特殊的白血病类型，预后极差。目前认为表观遗传学异常在MLL白血病的发生与发展中起着关键作用。因此，筛选受表观遗传学调控的基因或通路，是研究MLL白血病靶向治疗的重要方向。研究发现DNA甲基化可能参与MLL白血病的转化和维持，而靶基因的甲基化信息是由MBD蛋白识别并调控其表达的，提示MBD蛋白可作为研究DNA甲基化的切入点。因此本研究将利用已有的条件性MLL-AF6基因敲入小鼠模型和MBD2基因敲除小鼠模型，明确DNA甲基化在MLL白血病发病中的作用；同时，通过生物信息学分析，发掘受DNA甲基化调控的关键基因，并在小鼠模型中进行验证，从而为解析MLL白血病的表观遗传学机制和探索新的治疗靶点提供参考。