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Somatic mutation in  TET2  gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state,  TET2  mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge,  TET2  downregulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to  MIF  promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of  TET2 -decreased expression favors EGR1-driven transcription of  MIF  gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal  TET2  downregulation in myeloid cells.

Macrophage migration inhibitory factor is overproduced through EGR1 in TET2low resting monocytes