Loss-of-function mutations affecting one or both copies of the Ten-Eleven-translocation ( TET) 2 gene have been described in various human myeloid malignancies. We report that inactivation of Tet2 in mouse perturbs both early and late steps of hematopoiesis including myeloid and lymphoid differentiation in a cell-autonomous manner, endows the cells with competitive advantage, and eventually leads to the development of malignancies. We subsequently observed TET2 mutations in human lymphoid disorders. TET2 mutations could be detected in immature progenitors endowed with myeloid colony-forming potential. Our results show that the mutations present in lymphoid tumor cells may occur at both early and later steps of lymphoid development and indicate that impairment of TET2 function or/and expression predisposes to the development of hematological malignancies. ► TET2 inactivation in mice affects HSC homeostasis and differentiation ► TET2 inactivation in mice leads to a CMML-like disease ► TET2 is mutated in human B and T cell lymphomas