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

Elodie Pronier,François Delhommeau,Françoise Porteu,Maëla Francillette,Chloé Jego,Dorothée Selimoglu-Buet,Olivier A Bernard,Orianne Wagner-Ballon,Marie Breckler,Bouchra Badaoui,Daniel Gautheret,Thierry Roger,William Vainchenker,Aygun Imanci,Marine Aglave,Éric Solary ,María E Figueroa ,Raphaël Itzykson ,Audrey Naimo,Nathalie Droin

doi:10.1038/s42003-022-03057-w

Abstract

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.

Highlights

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)
Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in the peripheral blood of ageing healthy individuals, named Clonal Hematopoiesis of Indeterminate Potential (CHIP)[27]
We show that in CMML human monocytes harboring truncating variants of TET2 gene, MIF secretion is increased through EGR-1 transcription factor recruitment to its promoter

Summary

Introduction

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). TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in the peripheral blood of ageing healthy individuals, named Clonal Hematopoiesis of Indeterminate Potential (CHIP)[27]. These TET2-mutated clones can be a first step towards a malignancy such as CMML28.

Methods

Results

Conclusion