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Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

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Science  24 Feb 2017:
Vol. 355, Issue 6327, pp. 842-847
DOI: 10.1126/science.aag1381

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Faulty blood cells and heart disease

Recent studies have shown that elderly people's blood cells often harbor mutations in genes encoding certain epigenetic regulators. These mutations can lead to clonal expansion of the mutant blood cells, which increases the risk of blood cancers and cardiovascular disease. Fuster et al. generated a mouse model to investigate how one of these genes, Tet2, affects atherosclerosis development (see the Perspective by Zhu et al.). They found that the disease progressed more rapidly in mice transplanted with Tet2-deficient bone marrow cells. This was due to increased secretion of interleukin-1β by Tet2-deficient macrophages in a process that depended on the action of inflammasomes.

Science, this issue p. 842; see also p. 798

Abstract

Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of Tet2-mutant cells in atherosclerosis-prone, low-density lipoprotein receptor–deficient (Ldlr–/–) mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome–mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic TET2 mutations in blood cells play a causal role in atherosclerosis.

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