Non-catalytic Roles of Tet2 Are Essential to Regulate Hematopoietic Stem and Progenitor Cell Homeostasis

Summary: The Ten-eleven translocation (TET) enzymes regulate gene expression by promoting DNA demethylation and partnering with chromatin modifiers. TET2, a member of this family, is frequently mutated in hematological disorders. The contributions of TET2 in hematopoiesis have been attributed to its DNA demethylase activity, and the significance of its nonenzymatic functions has remained undefined. To dissect the catalytic and non-catalytic requirements of Tet2, we engineered catalytically inactive Tet2 mutant mice and conducted comparative analyses of Tet2 mutant and Tet2 knockout animals. Tet2 knockout mice exhibited expansion of hematopoietic stem and progenitor cells (HSPCs) and developed myeloid and lymphoid disorders, while Tet2 mutant mice predominantly developed myeloid malignancies reminiscent of human myelodysplastic syndromes. HSPCs from Tet2 knockout mice exhibited distinct gene expression profiles, including downregulation of Gata2. Overexpression of Gata2 in Tet2 knockout bone marrow cells ameliorated disease phenotypes. Our results reveal the non-catalytic roles of TET2 in HSPC homeostasis. : The DNA demethylase TET2 is commonly mutated in hematological disorders, but the significance of its enzymatic versus nonenzymatic roles in hematopoiesis remains undefined. Using Tet2 catalytic-mutant and knockout mice, Ito et al. find that Tet2 enzymatic activity is critical for myelopoiesis, while aberrant lymphopoiesis is mainly associated with complete loss of Tet2. Keywords: Tet2, 5-hydroxymethylcytosine, 5hmC, hematopoietic stem cells, HSCs, myelodysplastic syndrome, MDS, chronic lymphocytic leukemia, CLL