Loss-of-function mutations in Dnmt3a and Tet2 lead to accelerated atherosclerosis and concordant macrophage phenotypes.

Autor: Rauch PJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. philipp_rauch@dfci.harvard.edu.; Broad Institute of Harvard and MIT, Cambridge, MA, USA. philipp_rauch@dfci.harvard.edu., Gopakumar J; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Silver AJ; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Nachun D; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Ahmad H; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., McConkey M; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA., Nakao T; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Bosse M; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Rentz T; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Vivanco Gonzalez N; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Greenwald NF; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., McCaffrey EF; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Khair Z; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Gopakumar M; Department of Electrical Engineering, Stanford University, Stanford, CA, USA., Rodrigues KB; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Lin AE; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Sinha E; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Fefer M; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Cohen DN; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Vromman A; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Shvartz E; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Sukhova G; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Bendall S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Angelo M; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA., Libby P; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA., Ebert BL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Howard Hughes Medical Institute, Boston, MA, USA., Jaiswal S; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. sjaiswal@stanford.edu.; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA. sjaiswal@stanford.edu.
Jazyk: angličtina
Zdroj: Nature cardiovascular research [Nat Cardiovasc Res] 2023 Sep; Vol. 2 (9), pp. 805-818. Date of Electronic Publication: 2023 Sep 04.
DOI: 10.1038/s44161-023-00326-7
Abstrakt: Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the presence of a cancer-associated somatic mutation in white blood cells in the absence of overt hematological malignancy. It arises most commonly from loss-of-function mutations in the epigenetic regulators DNMT3A and TET2. CHIP predisposes to both hematological malignancies and atherosclerotic cardiovascular disease in humans. Here we demonstrate that loss of Dnmt3a in myeloid cells increased murine atherosclerosis to a similar degree as previously seen with loss of Tet2. Loss of Dnmt3a enhanced inflammation in macrophages in vitro and generated a distinct adventitial macrophage population in vivo which merges a resident macrophage profile with an inflammatory cytokine signature. These changes surprisingly phenocopy the effect of loss of Tet2. Our results identify a common pathway promoting heightened innate immune cell activation with loss of either gene, providing a biological basis for the excess atherosclerotic disease burden in carriers of these two most prevalent CHIP mutations.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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