Tet2, short for tet methylcytosine dioxygenase 2, is an α -ketoglutarate- and Fe2+-dependent dioxygenase in the ten-eleven translocation (TET) family. It catalyzes the iterative oxidation of 5-methylcytosine (5mC), playing a crucial role in DNA demethylation. This function is essential for normal hematopoiesis, especially myelopoiesis, and maintaining the balance between DNA methylation and demethylation in mammalian development and cell function, particularly in the hematopoietic system [1,3].

In KO/CKO mouse models, Tet2 loss leads to increased hematopoietic stem cell self-renewal in vivo, as shown by competitive transplant assays, eventually resulting in myeloproliferation including splenomegaly, monocytosis, and extramedullary hematopoiesis [4]. In oophorectomized (OVX) mice, Tet2 promotes bone loss and osteoclast differentiation by regulating autophagy [2]. Aging-related IL-1 signaling drives Tet2+/- clonal hematopoiesis, and inhibition of IL-1 signaling impairs Tet2+/- clonal expansion in mice [5]. Restoration of Tet2 expression in a transgenic RNAi mouse model reverses aberrant hematopoietic stem and progenitor cell self-renewal in vitro and in vivo, and vitamin C treatment mimics this effect [6].

In summary, Tet2 is fundamental for normal hematopoiesis, and its dysregulation is associated with hematological malignancies. Mouse models of Tet2 loss-of-function have been instrumental in revealing its role in hematopoietic transformation, bone loss, and clonal hematopoiesis, providing insights into the pathophysiology of related diseases and potential therapeutic targets.