The role of TET proteins in myeloid neoplasia

TET蛋白在骨髓瘤形成中的作用

• 批准号: 172168220
• 负责人: Professor Dr. Stefan Klaus Bohlander
• 金额: --
• 依托单位: Department of Molecular Medicine and Pathology
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/172168220?language=en
• 关键词: role; TET; proteins; myeloid; neoplasia

DNA methylation plays a central role in epigenetic gene regulation duringdevelopment and disease. Recently, 5-hydroxymethyl-cytosine (5hmC) wasdiscovered as a novel type of DNA modification catalyzed by TET oxygenases.Mutations in TET genes, especially in TET2, were recently identified in patients with avariety of myeloid neoplasias. However, it is still completely unknown how thesemutation cause hematopoietic transformation. In this joint research project, we willstudy the expression of the TET genes during normal hematopoiesis and in patientderived material at the RNA and protein level. We will use biochemical assays for TETprotein function and test whether TET mutations can have a dominant negative effect.We generate cell line and animal models for the MLL/TET1 fusion gene and TET2mutations. These models will answer the question whether TET alterations per se areable to trigger hematopoietic transformation and will provide material to study theunderlying, molecular mechanisms. This joint research project uniquely combinespatient data, biochemical and cell biology assay with animal models and is expectedto provide insight into a novel epigenetic pathway and its role in myeloid neoplasia.

DNA 甲基化在发育和疾病过程中的表观遗传基因调控中发挥着核心作用。最近，5-羟甲基胞嘧啶（5hmC）被发现是一种由 TET 加氧酶催化的新型 DNA 修饰。最近在多种骨髓瘤患者中发现了 TET 基因突变，特别是 TET2 突变。然而，这些突变如何引起造血转化仍然完全未知。在这个联合研究项目中，我们将在正常造血过程中以及患者来源的材料中在 RNA 和蛋白质水平上研究 TET 基因的表达。我们将使用生化检测来检测 TET 蛋白功能，并测试 TET 突变是否会产生显性负效应。我们为 MLL/TET1 融合基因和 TET2 突变生成细胞系和动物模型。这些模型将回答 TET 改变本身是否能够引发造血转化的问题，并将为研究潜在的分子机制提供材料。该联合研究项目独特地将患者数据、生化和细胞生物学测定与动物模型结合起来，预计将深入了解新的表观遗传途径及其在骨髓瘤形成中的作用。