Functions of TET-mediated oxidation of 5-methylcytosine in hematologic cancer

Abstract

Aberrant DNA methylation is a hallmark of cancer, and dysregulated DNA methylation-demethylation cycles is closely linked to the onset and progression of cancer. TET enzymes (TET1, TET2 and TET3) are Fe(II) and 2-ox- oglutarate-dependent dioxygenases that alter modification status of cytosines in DNA by successively oxidizing 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). Loss of TET functions and diminished genomic 5hmC levels are generally associated with oncogenic transformation in hematopoietic cancers as well as solid cancers. Particularly, TET2 gene is recurrently deleted or mutated in a wide spectrum of hematologic malignancies including myeloid and lymphoid malignancies. In this talk, I will present our recent findings on the role of TET proteins in normal and malignant hematopoietic development, with an em- phasis on the previously unappreciated functions of TET proteins in controlling cell lineage commitment and genome integrity during hematopoiesis. Together with the observations that TET proteins are key player of tumor growth and invasion, these studies suggest that manipulation of TET functions may provide new avenues to develop novel epigenetic therapies for treating cancers.