HIF1a通过调控RNA甲基化(m6A)活化KIT通路促进AML发生的新机制

携带KIT突变的t(8;21)AML预后不良，我们前期发现抑制t(8;21)AML中异常高表达的缺氧诱导因子1a（HIF1a）能抑制KIT表达及细胞增殖，机制未明。Wilms’瘤1-关联蛋白（WTAP）是关键的RNA甲基化（m6A）修饰酶之一，与白血病发生关系密切。我们发现，t(8;21)AML患者中WTAP分别与HIF1a、KIT基因表达呈正相关，故三者之间可能存在调控关系；且由于WTAP高表达的t(8;21)AML患者生存期短，我们设想HIF1a可能通过调控WTAP介导的RNA甲基化分布间接活化KIT信号通路促进白血病发生。.本项目拟阐明HIF1a通过WTAP-m6A激活KIT信号通路的分子网络，分析异常RNA甲基化分布促进白血病发生的潜在机制，观察靶向药物对上述通路异常活化的抑制效应。研究结果有助于加深对t(8;21)AML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。

The KIT mutated patients with t(8;21) acute myeloid leukemia (AML) have a poor prognosis. Hypoxia inducible factor 1a (HIF1a) was highly expressed in t(8;21) AML. Our preliminary results showed that downregulation of HIF1a expression could inhibit the expression of KIT and cellular proliferation. But the underlying mechanism remains unknown. Wilms’ tumor 1-associating protein (WTAP), a key regulatory subunit of the RNA N6-methyladenosine (m6A) methyltransferase, has a close relationship with leukemogenesis. We found that WTAP mRNA expression in t(8;21) AML patients was positively correlated with the mRNA expression levels of HIF1a and KIT, suggesting a potential regulatory relationship among these genes. Because WTAP was selectively up-regulated in t(8;21) AML and correlated with a poor prognosis, we hypothesized that HIF1a facilitated to drive the occurrence of t(8;21) AML by governing WTAP-mediated RNA methylation program and its downstream KIT signaling pathway..The present study was designed to demonstrate the molecular interaction between HIF1a and WTAP-m6A in regulating KIT activation, investigate a potential mechanistic pathway linking aberrant RNA methylation pattern and leukemia occurrence, and test the efficiency of targeted agents on blocking the above-mentioned pathway. The results would provide the theoretical and experimental foundation for better understanding the mechanisms of occurrence of t(8;21) AML and developing new therapeutic targets.