RNA甲基化沉默Tnfrsf1b促进t(8;21)AML发生的机制研究

t(8;21)在急性髓细胞白血病(AML)发生中起重要作用，但还需其他遗传或表观遗传事件协同方能致病。RNA甲基化修饰(m6A)与白血病有关。Tnfrsf1b基因通过介导细胞坏死性凋亡抑制白血病，m6A结合蛋白YTHDF2能识别并降解m6A修饰的Tnfrsf1b mRNA。我们发现t(8;21)AML中，YTHDF2呈高表达而Tnfrsf1b低表达，沉默YTHDF2能增加m6A、上调Tnfrsf1b、抑制白血病细胞增殖。故设想YTHDF2通过促进依赖m6A修饰的Tnfrsf1b降解，阻止t(8;21)白血病前体细胞死亡，促发白血病。.本项目拟阐明t(8;21)AML中RNA甲基化介导Tnfrsf1b及下游细胞死亡信号通路沉默的分子机制，分析Tnfrsf1b沉默与白血病的关系，探索抑制上述信号通路对白血病的疗效。结果有助于加深对白血病发病机制的认识，也为开发治疗新靶点提供实验基础和理论依据。

Despite the causative role of the t(8;21) translocation in leukemia initiation, additional genetic or epigenetic events are required for disease development. Aberrant RNA methylation (N6-methyladenosine, m6A) is closely associated with leukemia initiation. The protein encoded by Tnfrsf1b gene inhibits the accumulation of leukemia cells by inducing cellular necroptosis. The YTHDF2, a m6A binding protein, is able to bind and degrade m6A-modified Tnfrsf1b mRNA. We found that YTHDF2 was highly expressed but Tnfrsf1b was lowly expressed in t(8;21) AML patients. Silencing YTHDF2 could increase the overall m6A levels, up-regulate the level of Tnfrsf1b mRNA expression, and inhibit the cellular proliferation in t(8;21) AML cells. We therefore hypothesized that YTHDF2 might play a role in promoting the development of leukemia by inhibiting cell death of t(8;21)-positive leukemia precursor cells through enhancing the m6A-dependent degradation of Tnfrsf1b mRNA..The current project intends to elucidate the molecular mechanism of abnormal RNA methylation-mediated silencing of Tnfrsf1b and its downstream cellular death signaling pathway in t(8;21) AML, analyze the relationship between silence of Tnfrsf1b expression and leukemia development, and explore the therapeutic effects of inhibiting the above signaling pathway on leukemia. The results will be benefit to understanding of the mechanisms of leukemogenesis, and also provide experimental and theoretical basis for the development of new targets for leukemia treatment.