TET2通过BER/MMR途径调控血液髓系肿瘤的研究

TET2 mutation is essential and critical for the pathogenesis and prognosis of myeloid malignancy. Our previous studies identify that TET2 associates with components of BER and MMR proteins. We also find that TET2 loss may impair the efficiency of DNA damage repair, leading to increased DNA mutagenicity in HSC/HPC, which paly an important role in the pathogenesis and progression of myeloid malignancies. These findings provide a framework for further studies. First, the roles of TET2 depended DNA methylation in gene expression profile, mutation profile and pathogenesis will be illustrated. Next, we will study the roles and mechanisms of key genes regulating the pathogenesis and progression of myeloid malignancies. Moreover, we will identify the roles of TET2 regulation in safeguarding genomic mutagenicity and DNA damage repair by BER/MMR. Last, clarifying the roles of BER/MMR inhibitors for hematological myeloid malignancies with TET2 mutations will be studied. Advances in our knowledge of the roles of TET2 regulation in safeguarding genomic mutagenicity by BER/MMR, coupled with an improved understanding of the role and mechanism of TET2 loss on the progression and prognosis of myeloid malignancies, will probably lead to the development of additional therapies and multivariate risk classification that improve outcomes for hematological malignancy patients with TET2 mutations.

TET2是表观遗传学调控最重要的蛋白酶，其异常是血液髓系肿瘤重要的发病、进展及预后因素。我们前期实验证实TET2和BER/MMR等主要DNA损伤修复途径中的关键蛋白存在关联。此外，TET2缺失阻碍DNA损伤修复，导致HSC/HPC基因组稳定性差和突变率增加，促使血液髓系肿瘤发生和进展。本课题在前期实验基础上，进行如下研究: 1、阐明TET2调控的甲基化修饰与基因表达、基因突变和疾病发生的相互关联；2、揭示调控血液髓系肿瘤类型及进展的关键基因群及相关机制；3、明确BER/MMR途径在TET2调控基因组稳定性和DNA损伤修复中的作用；4、探寻BER/MMR抑制剂治疗TET2突变血液髓系肿瘤的作用。本研究通过探索TET2通过BER/MMR途径发挥调控基因组稳定性作用，阐明其在血液髓系肿瘤发生和进展中的作用，建立血液髓系肿瘤预后分层新模式，验证治疗TET2突变血液髓系肿瘤的新方案。

TET2是表观遗传学调控最重要的蛋白酶，其异常是血液髓系肿瘤重要的发病、进展及预后因素。我们前期实验证实TET2和BER/MMR等主要DNA损伤修复途径中的关键蛋白存在关联。此外，TET2缺失阻碍DNA损伤修复，导致HSC/HPC基因组稳定性差和突变率增加，促使血液髓系肿瘤发生和进展。本课题在前期实验基础上，进行如下研究: 1、阐明TET2调控的甲基化修饰与基因表达、基因突变和疾病发生的相互关联；2、揭示调控血液髓系肿瘤类型及进展的关键基因群及相关机制；3、明确BER/MMR途径在TET2调控基因组稳定性和DNA损伤修复中的作用；4、探寻BER/MMR抑制剂治疗TET2突变血液髓系肿瘤的作用。本研究通过探索TET2通过BER/MMR途径发挥调控基因组稳定性作用，阐明其在血液髓系肿瘤发生和进展中的作用，建立血液髓系肿瘤预后分层新模式，验证治疗TET2突变血液髓系肿瘤的新方案。