Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

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.

Epigenetic dysregulation of hematopoietic stem cells and preleukemic state

“…Rather, the most significant cause of decreased overall survival associated with CHIP was an increased propensity for smoking, thrombosis, and cardiovascular diseases, including coronary artery disease and stroke [12,13]. Indeed, atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr −/− ) mice reconstituted with Tet2-deficient BM cells led to clonal hematopoietic expansion and a marked increase in atherosclerotic plaque in vivo due to increased NLRP3 inflammasome-mediated interleukin-1β secretion in Tet2-deficient macrophages, providing functional relevance of somatic TET2 mutations in hematopoietic cells in atherosclerosis development [14]. These data indicate that, although clonal genetic changes or cooperating mutations may lead to alteration of normal hematopoiesis, clonal hematopoiesis per se may not be sufficient to engender preleukemic state, which evolves with high frequency into full-blown leukemia.…”

CMML: Clinical and molecular aspects

“…Non-cell autonomous mechanisms involving dialogue between clonal differentiated cells and clonal HSCs, or between leukemic cells and the micro-environment may also contribute to the disease. For instance, TET2-deficient macrophages have increased NLRP3 inflammasome-mediated interleukin-1β secretion [47], and interleukin-1β have been suggested to contribute to leukemic cell expansion [48].…”

Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

“…13 CHIP patients appear to specifically have an increased risk of atherosclerotic heart disease. 15,16 It is not known whether this cardiovascular risk is specific to CHIP, or whether patients with similar mutations and with an MDS diagnosis also carry this increased risk.…”