阿片受体信号通路调节急性髓系白血病DNA羟甲基化的作用机制及治疗应用

Acute myeloid leukemia (AML), the most common acute leukemia in adult, is a heterogeneous disease. Many AML subtypes indicate poor prognosis. It is urgently needed to better understand the mechanism of AML, and develop novel targeted therapy based on such understanding. The Ten-eleven translocation (TET) proteins (TET1/2/3) can convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and have been shown to be critically involved in AML. TET2 is known as a tumor suppressor in AML, but it remains unclear how TET2 is regulated. We recently found: In AML cells, downregulation of μ-opioid receptor (OPRM1) resulted in a decreased expression of TET2. OPRM1 agonists significantly inhibited AML cell viability, while increased TET2 expression and cellular DNA 5hmC level. Here we hypothesize: OPRM1 signaling plays a critical role in AML pathogenesis through regulating 5hmC modification at its target gene loci, and OPRM1 agonists hold therapeutic potential in treating AML. We plan to further investigate: 1) The role of OPRM1 in AML; 2) The molecular mechanism and network of OPRM1 signaling in regulating TET2 expression and 5hmC modification of targeted genes in AML; 3) The therapeutic potential of OPRM1 agonists in treating AML. Our study will determine the definitive role and epigenetic mechanism of opioid receptor signaling in AML pathogenesis, and develop novel therapies targeting OPRM1/TET2 axis to treat AML.

急性髓细胞性白血病(AML)是成人最常见的急性白血病，多种亚型预后不佳，急需进一步了解AML的发病机理，发展高效特异靶向治疗。TET家族介导的DNA 5-羟甲基化（5hmC）修饰与白血病的发生发展密切相关。其中，TET2是一个关键抑癌基因，其在AML中的调节机制尚未明确。我们发现：AML细胞中抑制OPRM1，明显抑制TET2表达。OPRM1激动剂抑制AML细胞活性，增加TET2表达，提高DNA 5hmC水平。我们假设：OPRM1信号通路通过调节靶基因5hmC修饰在AML中发挥关键作用，其激动剂可能可治疗AML。计划进一步研究：1）OPRM1在AML中的作用；2）AML中阿片受体调控TET2表达和靶基因5hmC修饰的分子机制及调控网络；3）阿片受体激动剂在AML中的治疗应用。以上研究将揭示阿片受体信号通路在AML中的表观遗传学作用和机制，并发掘靶向OPRM1/TET2调控轴的AML新疗法。

急性髓细胞性白血病(AML)是成人最常见的急性白血病，多种亚型预后不佳，急需进一步了解AML的发病机理，发展高效特异靶向治疗。TET家族介导的DNA 5-羟甲基化（5hmC）修饰与白血病的发生发展密切相关。其中，TET2是一个关键抑癌基因，其在AML中的调节机制尚未明确。我们前期研究发现：AML细胞中抑制OPRM1，明显抑制TET2表达。OPRM1激动剂抑制AML细胞活性，增加TET2表达，提高DNA 5hmC水平。我们假设：OPRM1信号通路通过调节靶基因5hmC修饰在AML中发挥关键作用，其激动剂可能可治疗AML。在此基础上，本项目进一步研究并揭示了：1）阿片受体激动剂在体和体外对AML细胞活性的显著抑制：阿片受体激动剂OPA1对多种AML细胞和小鼠AML有显著抑制；2）AML中阿片受体信号通路通过EGR1等转录因子调控TET2表达，进而通过5hmC修饰和酶活性非依赖功能，调节NFkB等靶通路活化；3）阿片受体激动剂在人源AML中表现出较好疗效，以及与化疗药的协同疗效。本研究首次发现并系统报道了阿片受体激动剂对AML的潜在疗效，揭示了阿片受体信号通路对TET介导的表观遗传学修饰的全新调控，阐释了TET在阿片受体激动剂治疗过程中表现出的激酶活性依赖和非依赖的双重功能，提示以洛哌丁胺为代表的阿片受体激动剂"老药新用"治疗白血病的可能性。