The role of TET proteins in myeloid neoplasia

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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.