RNA-m6A去甲基化酶FTO调控MELK促进慢性淋巴细胞白血病发生发展的机制

慢性淋巴细胞白血病（CLL）是一种异质性强的不可治愈性肿瘤，其发病机制尚不明确。申请人前期研究发现MELK在CLL发生发展中起重要作用，但具体调控机制仍不清楚。本项目已初步证实：CLL细胞中RNA-m6A甲基化程度差异性下降；RNA-m6A去甲基化酶FTO与MELK的mRNA表达量呈正相关；抑制FTO活性可显著下调MELK表达且减慢CLL细胞增殖等功能。本项目拟进一步探讨：①依托CLL临床样本大数据平台，探究CLL病人中MELK、FTO表达和m6A甲基化程度及临床意义；②体外揭示FTO调控MELK的RNA-m6A去甲基化对CLL细胞增殖等功能的影响及机制；③动物体内验证FTO调控MELK表达的作用机制。目的为阐明FTO介导RNA-m6A甲基化调控MELK在CLL发生发展的作用机制，为新型MELK靶向干预策略在CLL的应用提供理论依据，具有重要的科学意义和转化价值。

Chronic lymphocytic leukemia (CLL) is a highly heterogeneous and incurable malignancy, of which the pathogenesis remains unclear. Our previous studies identified that MELK exerted crucial roles in the tumorigenesis and progression of CLL. However, the regulatory mechanisms of MELK in CLL are poorly understood. We have preliminarily confirmed that RNA N6-methyladenosine (m6A) methylation levels were differentially decreased in CLL cells. Additionally, FTO, an RNA-m6A demethylase, was found in positive correlation with MELK expression at mRNA levels. Moreover, inhibition of FTO activity significantly down-regulated MELK expression and attenuated proliferation of CLL cells. This project is proposed to further explore in the following three aspects: ① Based on the CLL specimen database, the levels of MELK expression, FTO expression and RNA-m6A, together with their clinicopathological significance will be investigated in CLL patients; ② In vitro studies will be conducted to reveal the effects and mechanisms of FTO regulating MELK on CLL cell proliferation and other functions via RNA-m6A demethylation; ③ In vivo studies are to verify the effects and mechanisms of FTO modulating MELK expression in CLL mice models. The aim of the project is to elucidate the mechanisms of FTO promoting MELK expression through RNA-m6A demethylation in the tumorigenesis and progression of CLL. It highlights important scientific significance and translational value, providing theoretical basis of novel MELK-targeted strategies as therapeutic approaches for CLL patients.