THAP10/EZH2/C-KIT轴参与t(8;21)急性髓系白血病发生发展的机理研究

THAP10 with THAP domain structure, and is one of members of the family which newly discovered THAP proteins. With the support of the national natural science foundation of China, the applicant has studied the regulation mechanism of THAP10 at the transcriptional level and translation level, and the roles of which inhibiting proliferation and promoting apoptosis that it played in t(8;21) acute myeloid leukemia was also confirmed, and the article was published in EMBO Mol Med. However, being a transcription factor, the downstream target genes and which signal pathway regulated by THAP10 are not clear. Our preliminary experiments confirmed that the epigenetic silence of THAP10 relieved the inhibition of c-myc and NF-kappa B, and then activated EZH2. On the other hand, AML1/ETO can remove miR-124-3p by epigenetics silencing and disinhibition of EZH2 at the level of translation. In the regulation mechanism of C-kit, EZH2 activated C-kit in a way that was independent on PRC2. Meanwhile, the epigenetic silencing THAP10 relieved the inhibition of C-kit, resulting in t(8;21)AML leukemogenesis. To elucidate the mechanism of THAP10/EZH2/C-KIT axis in t(8;21)AML, and to understand the mechanism of leukemia, it provide new means and strategies for clinical diagnosis and treatment in the future.

核转录因子THAP10是新发现的THAP蛋白家族成员之一。在已结题国家自然科学基金支持下，申请人对THAP10在转录水平和翻译水平上的调控机制进行了研究，其在t(8;21)AML中抑制增殖和促进凋亡的功能也得到证实，文章发表于EMBO Mol Med。但THAP10作为转录因子，其所调控的下游靶基因及信号通路尚不清楚。初步试验证实，THAP10的表观遗传学沉默解除了其对C-Myc和NF-κB的抑制，进而活化EZH2；另一方面，AML1/ETO可以通过表观遗传学沉默miR-124-3p，解除其对EZH2在翻译水平的抑制。在C-KIT的调控机制上，EZH2以非依赖PRC2的方式活化C-KIT，同时，表观遗传学沉默的THAP10解除了对C-KIT的抑制，导致t(8;21)AML的发生发展。阐明THAP10/EZH2/C-KIT轴的作用机制，深入认识白血病的发生机理，为临床诊治提供新的手段和策略。

表观遗传学和遗传学是白血病多因素多步骤致病机制中的重要组成部分。前期，我们通过全基因组甲基化芯片对t(8;21)AML临床样本进行分析，发现抑癌基因THAP10。申请人的系列研究证实：1）AML1/ETO对THAP10的表观遗传学沉默机制；2）AML1/ETO还可以通过募集p300实现对miR-383的表观遗传学激活，高表达的miR-383进一步抑制THAP10的表达；3）明确了THAP10在t(8;21)AML中发挥了抑癌基因的功能。虽然我们对THAP10的转录和翻译水平的调控机制有了较为深入的认识，但是，THAP10发挥这些功能是通过什么信号途径？其所调控的下游靶基因是什么？THAP结构域在THAP10发挥这些功能中的作用是什么？这些问题一直是THAP蛋白家族研究的前沿。本项目通过深入研究证实：THAP10/EZH2/C-KIT轴在t(8;21)AML的发生发展中发挥了重要的作用。在EZH2的调控机制上：在正常的CD34髓系细胞中，THAP10通过抑制C-Myc和NF-κB的表达，从而抑制了EZH2的活化；AML1-ETO通过表观遗传学机制使THAP10表达沉默，从而解除了对C-Myc和NF-κB的抑制，使EZH2发生转录活化；另一方面，AML1-ETO可以通过表观遗传学沉默miR-124-3p，解除miR-124-3p对EZH2在翻译水平的抑制，这两方面的作用都是为了使EZH2的表达升高。在C-KIT的调控机制上：一方面，表达增高的EZH2可以使C-KIT活化；另一方面，表观遗传学沉默的THAP10解除了对C-KIT的抑制，从而使C-KIT的表达升高，并导致t(8;21)AML的发生发展。这为阐明THAP10表观遗传学调控与t(8;21)AML的发生和复发奠定了基础，同时，也为我们理解复杂的基因调控网络提供新的视角，为白血病的临床诊断、预后和治疗提供新的手段和策略。