Multitargeted Reduction of Inflammation and Atherosclerosis in Tet2-deficient CHIP via XPO1 Inhibition and Atf3 restoration

Abstract

TET2 is the second most frequently mutated gene in clonal hematopoiesis of indeterminate potential (CHIP), driving hematopoietic stem cell clonal expansion and increasing the risk of myeloid malignancies. Affected individuals often develop atherosclerotic cardiovascular disease, exacerbated by hyperinflammatory TET2-mutant macrophages. Here, we show that the XPO1 nuclear export inhibitor eltanexor significantly reduces atherosclerotic plaque formation in a mouse model of Tet2-mutant CHIP. In addition, we investigated the mechanisms and gene expression pathways that underlie the proinflammatory phenotype that characterizes Tet2-mutant CHIP. Single-cell CITE-seq identified increased expression of multiple proinflammatory mediators in Tet2-mutant macrophages and in non-hematopoietic cells of the aortic wall, which was reduced by eltanexor treatment. Atf3, which encodes a core transcriptional modulator of inflammation, occupies and regulates the largest enhancer in wild-type macrophages. Tet2 loss diminished ATF3 binding to the regulatory loci of inflammatory mediators, which was restored upon XPO1 inhibition. These results provide new insights into drivers of heightened inflammation in TET2-mutant CHIP and highlight a novel therapeutic strategy for intervention.