Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice

Fuster, José J., MacLauchlan, Susan, Zuriaga, María A., Polackal, Maya N., Ostriker, Allison C., Chakraborty, Raja, Wu, Chia-Ling, Sano, Soichi, Muralidharan, Sujatha, Rius, Cristina, Vuong, Jacqueline, Jacob, Sophia, Muralidliar, Varsha, Robertson, Avril A. B., Cooper, Matthew A., Andres, Vicente, Hirschi, Karen K., Martin, Kathleen A. and Walsh, Kenneth (2017) Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice. Science, 355 6327: 842-847. doi:10.1126/science.aag1381

Author Fuster, José J.
MacLauchlan, Susan
Zuriaga, María A.
Polackal, Maya N.
Ostriker, Allison C.
Chakraborty, Raja
Wu, Chia-Ling
Sano, Soichi
Muralidharan, Sujatha
Rius, Cristina
Vuong, Jacqueline
Jacob, Sophia
Muralidliar, Varsha
Robertson, Avril A. B.
Cooper, Matthew A.
Andres, Vicente
Hirschi, Karen K.
Martin, Kathleen A.
Walsh, Kenneth
Title Clonal hematopoiesis associated with Tet2 deficiency accelerates atherosclerosis development in mice
Journal name Science   Check publisher's open access policy
ISSN 1095-9203
Publication date 2017-02-24
Year available 2017
Sub-type Article (original research)
DOI 10.1126/science.aag1381
Open Access Status Not yet assessed
Volume 355
Issue 6327
Start page 842
End page 847
Total pages 6
Place of publication Washington, DC, United States
Publisher American Association for the Advancement of Science
Language eng
Subject 1000 General
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-1b 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.
Keyword Subclinical Atherosclerosis
Somatic Mutations
Myeloid Cancers
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 17SDG33400213
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Institute for Molecular Bioscience - Publications
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