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

• DOI: 10.1016/j.celrep.2019.07.094
• Publication Date: 2019-09-03T14:48:34Z
• Authors: Kyoko Ito; Joun Lee; Stephanie Chrysan...; Yilin Zhao; Katherine Josephs; Hiroyo Sato; Julie Teruya-Feld...; Deyou Zheng; Meelad M. Dawlaty; Keisuke Ito
• Keywords: Homeostasis; Hematopoietic stem cell; Progenitor

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. contributions TET2 hematopoiesis have been attributed to its demethylase activity, the significance nonenzymatic functions has remained undefined. To dissect catalytic non-catalytic requirements Tet2, we engineered catalytically inactive Tet2 mutant mice conducted comparative analyses knockout animals. exhibited expansion hematopoietic stem progenitor cells (HSPCs) developed myeloid lymphoid disorders, while predominantly malignancies reminiscent human myelodysplastic syndromes. HSPCs from distinct profiles, including downregulation Gata2. Overexpression Gata2 bone marrow ameliorated disease phenotypes. Our results reveal roles HSPC homeostasis.