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Somatic loss-of-function mutations of the dioxygenase Ten-eleven translocation-2 (TET2) occur frequently in individuals with clonal hematopoiesis (CH) and acute myeloid leukemia (AML). These common hematopoietic disorders can be recapitulated in mouse models. However, the underlying mechanisms by which the deficiency in TET2 promotes these disorders remain largely unknown. Here we show that the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway is activated to mediate the effect of TET2 deficiency in leukemogenesis in mouse models. DNA damage arising inTet2-deficient hematopoietic stem/progenitor cells (HSPCs) leads to activation of the cGAS-STING pathway which in turn induces the development of CH and myeloid transformation. Notably, both pharmacological inhibition and genetic deletion of STING suppressesTet2mutation-induced aberrant myelopoiesis. In patient-derived xenograft (PDX) models, STING inhibition specifically attenuates the proliferation of leukemia cells from TET2-mutated individuals. These observations suggest that the hematopoietic transformation associated with TET2 mutations is powered through sterile inflammation dependent on the activated cGAS-STING pathway, and that STING may represent a potential target for intervention of relevant hematopoietic malignancies.Key pointsTet2deficiency leads to DNA damage which in turn activates the cGAS-STING pathway to induce an inflammatory responseBlocking STING in TET2-mutated hematopoietic stem/progenitor cells suppresses clonal hematopoiesis in mice and leukemogenesis in patient-derived xenograft models