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

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. © 2022. The Author(s).

Citation

Elodie Pronier, Aygun Imanci, Dorothée Selimoglu-Buet, Bouchra Badaoui, Raphael Itzykson, Thierry Roger, Chloé Jego, Audrey Naimo, Maëla Francillette, Marie Breckler, Orianne Wagner-Ballon, Maria E Figueroa, Marine Aglave, Daniel Gautheret, Françoise Porteu, Olivier A Bernard, William Vainchenker, François Delhommeau, Eric Solary, Nathalie M Droin. Macrophage migration inhibitory factor is overproduced through EGR1 in TET2low resting monocytes. Communications biology. 2022 Feb 03;5(1):110

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PMID: 35115654

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