INSERM U1287, Gustave Roussy Cancer Center, 94805, Villejuif, France.
Owkin Lab, Owkin, Inc., New York, NY, 10003, USA.
Commun Biol. 2022 Feb 3;5(1):110. doi: 10.1038/s42003-022-03057-w.
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.
TET2 基因体细胞突变是与年龄相关的克隆性造血以及慢性粒单核细胞白血病（CMML）相关的最常见的克隆性遗传事件之一。除了是一种癌前状态外，TET2 突变克隆与心血管疾病死亡风险增加相关，这可能涉及单核细胞过度产生细胞因子/趋化因子。在这里，我们在小鼠和人类细胞中表明，在没有任何炎症挑战的情况下，TET2 下调会促进 MIF（巨噬细胞迁移抑制因子）的产生，MIF 是动脉粥样硬化病变形成的关键介质。在健康的单核细胞中，TET2 被招募到 MIF 启动子并与转录因子 EGR1 和组蛋白去乙酰化酶相互作用。由于 TET2 表达减少而破坏这些相互作用有利于 EGR1 驱动 MIF 基因的转录及其分泌。MIF 有利于骨髓祖细胞向单核细胞的分化。这些结果将 MIF 指定为一种慢性过度产生的趋化因子，并且是骨髓细胞中克隆性 TET2 下调的患者的潜在治疗靶点。
