PTCH1基因甲基化与Hedgehog信号通路活化在急性髓系白血病中的作用机制

Epigenetic alterations marked by DNA methylation are known to be frequent events during the development of acute myeloid leukemia (AML).Discovering new abnormal gene methylation patterns are significant for the diagnosis and treatment of AML. We have preliminarily found that: ①Hedgehog signaling pathway was aberrantly activated in AML; ②PTCH1, the membrane receptor of Hh signaling pathway, was hypermethylated and down-regulated expressed in some of AML samples. But it is still uncleared about the molecular mechanism of PTCH1 methylation and Hh pathway activation in the leukemogenesis of AML. This study is aimed to clarify the expression and hypermethylated modification of PTCH1 in AML cells; investigate the role of PTCH1 in regulating cell growth by using AML cell lines and AML mouse model; explore molecular mechanism of PTCH1 methylation and Hh pathway activation; identify the correlation of PTCH1 expression level and the methylation status of PTCH1 promoter with clinical characteristics and prognosis in AML. These data may reveal the PTCH1 methylation and Hh pathway activation in the pathogenesis and development of AML, so that to provide insights into the diagnosis, prognosis and treatment of AML.

表观遗传学改变如DNA甲基化与急性髓系白血病（AML）的发生密切相关。在AML中发现新的基因甲基化异常对其诊断及治疗具有重要意义。我们的前期研究发现①Hedgehog（Hh）信号通路在AML中存在异常激活；②Hh信号通路膜受体PTCH1 mRNA在部分AML细胞中表达降低，启动子区域存在高甲基化。但我们对PTCH1基因甲基化异常与Hh信号通路活化在AML发病中的作用和分子机制并不清楚。本项目拟进一步明确PTCH1在AML中的表达及甲基化调控；在AML细胞系和AML小鼠模型中研究PTCH1对AML细胞生长的作用；探究PTCH1甲基化与AML中Hh信号通路激活的分子机制；分析AML患者标本PTCH1的表达水平及甲基化状态与临床特征的关系。通过上述研究揭示PTCH1甲基化与Hh信号通路活化在AML发生、发展中的作用，并为AML的早期诊断、预后判断和靶向治疗提供新的思路。

表观遗传学改变如DNA甲基化与急性髓系白血病（AML）的发生密切相关。本项目发现AML中PTCH1基因启动子区域高甲基化修饰而表达下调，AML患者标本中PTCH1低表达与AML预后差呈正相关。维生素C能够通过增强组蛋白去甲基化转移酶JMJD3的活性，与EZH2抑制剂DZNep共同下调H3K27me3水平，重激活PTCH1表达，抑制AML细胞增殖，促使其凋亡、分化。我们进一步发现在PTCH1低表达患者使用维生素C联合DZNep的表观遗传治疗可能改善患者预后。以上结果为AML诊疗靶点提供新的依据，为维生素C联合DZNep的表观遗传治疗提供新的思路。