THAP10的表观遗传学沉默参与t(8;21)急性髓系白血病发生的机制研究

THAP10 with THAP domain structure, and are members of the family of newly discovered THAP proteins, its regulatory mechanism is not clear. In our previous articles published on "Blood", of which epigenetic regulation of miR-193a was elucidated. On the basis of using methylation chip screening, we identified that THAP10 is high methylation in t(8;21) acute myeloid leukemia samples. Bioinformatics analysis and preliminary experiments confirmed that lower expression level of THAP10 is likely affected by two factors: on the one hand, the fusion protein AML1/ETO make THAP10 epigenetic silent by recruiting epigenetic enzymes; miR-383, on the other hand, inhibits the expression of THAP10 through its 3'-UTR. Both of them belong to the category of epigenetic and they work together to make THAP10 with low expression in AML patient leukemia cell; promote the abnormal cell proliferation, leading to the occurrence of leukemia. In addition, preliminary study of the THAP10 structure and function, together with elucidation of the epigenetic regulatory mechanisms in t(8;21) AML, laid a foundation for the mechanism of the occurrence and recurrence of AML, also provides a new angle of view for us to fully understand the complex gene regulation network, in the end of clinical diagnosis of leukemia and other cancers, which can be successfully targeted by pharmacological treatment using de-epigenetic agents in t(8;21)-leukemias.

THAP10是新发现的THAP蛋白家族成员，其调控机制尚不清楚。在我们前期《Blood》文章对miR-193a的表观遗传学调控基础上，利用甲基化芯片筛选到THAP10在t(8;21)AML中是高甲基化的。生物信息学分析及初步试验证实THAP10的表达降低受两方面因素的影响：一方面，AML1/ETO通过募集表观遗传学修饰酶使THAP10表达沉默；另一方面，miR-383对THAP10的抑制。而miR-383的表达增高很可能是由于AML1/ETO募集了P300使miR-383的启动子区发生了乙酰化。这两方面都属于表观遗传学范畴，它们的共同作用使THAP10在AML患者细胞中低表达,促进细胞异常增殖，导致白血病的发生。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。

THAP10是新发现的THAP蛋白家族成员，其调控机制尚不清楚。在我们前期《Blood》文章对miR-193a的表观遗传学调控基础上，利用甲基化芯片筛选到THAP10在t(8;21)AML中是高甲基化的。生物信息学分析及初步试验证实THAP10的表达降低受两方面因素的影响：一方面，AML1/ETO通过募集表观遗传学修饰酶使THAP10表达沉默；另一方面，miR-383对THAP10的抑制。而miR-383的表达增高很可能是由于AML1/ETO募集了P300使miR-383的启动子区发生了乙酰化。本项目通过深入研究证实：1，大量临床样本检测发现，THAP10的表达和融合基因AML1/ETO的表达呈负相关，在AML1/ETO阳性的临床样本中，THAP10低表达预示着病人预后较差；2，融合蛋白AML1/ETO可以结合在THAP10启动子区，并且募集HDACs和DNMTs，从而使THAP10在转录水平上发生表观遗传学沉默；3，THAP10在翻译水平上受miR-383的调控，而miR-383的转录受融合蛋白AML1/ETO的正向调控；这两方面都属于表观遗传学范畴，它们的共同作用使THAP10在AML患者细胞中低表达,促进细胞异常增殖，导致白血病的发生。进一步，本项目也证实，THAP10是一个定位在细胞核内的抑癌基因，在t(8;21)AML中发挥了抗凋亡和促分化作用。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。