The role of TET proteins in myeloid neoplasia

DNA甲基化在发育和疾病的表观遗传基因调控中起着核心作用。近年来，5-羟甲基胞嘧啶(5hmC)被发现是一种新型的由Tet加氧酶催化的DNA修饰，在各种髓系肿瘤患者中发现了Tet基因的突变，尤其是TET2。然而，目前还完全不清楚这种突变是如何导致造血转化的。在这个联合研究项目中，我们将从RNA和蛋白质水平研究Tet基因在正常造血过程中和患者来源材料中的表达。我们将使用生化分析来检测TET蛋白的功能，并测试TET突变是否会产生显性的负面影响。我们建立了MLL/TET1融合基因和TET2突变的细胞系和动物模型。这些模型将回答Tet改变本身是否能够触发造血细胞转化的问题，并将为研究其潜在的分子机制提供材料。这一联合研究项目独一无二地将患者数据、生化和细胞生物学分析与动物模型相结合，有望为深入了解一种新的表观遗传途径及其在髓系肿瘤中的作用提供依据。

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.