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      Recurrent Aortic Thromboembolism Associated With TET2 Mutation in Chronic Myelomonocytic Leukemia

      case-report

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          Abstract

          Ten-eleven translocation 2 ( TET2) plays a pivotal role in epigenetic regulation, cell differentiation, and the inflammatory response. It also mediates the transcriptional regulation for inflammatory cytokines, particularly interleukin-6. While loss-of-function mutation in TET2 has been associated with hematological malignancies, it has been increasingly recognized to cause atherosclerotic disease. The increased atherogenicity is thought to be the result of increased production of pro-inflammatory interleukin-1β cytokines following activation of NLRP3 inflammasomes. We present a unique case of recurrent atherothrombosis in an elderly man who was diagnosed with chronic myelomonocytic leukemia in the setting of TET2 mutation.

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          Age-related clonal hematopoiesis associated with adverse outcomes.

          Siddhartha Jaiswal, Pierre Fontanillas, Jason Flannick … (2014)
          The incidence of hematologic cancers increases with age. These cancers are associated with recurrent somatic mutations in specific genes. We hypothesized that such mutations would be detectable in the blood of some persons who are not known to have hematologic disorders. We analyzed whole-exome sequencing data from DNA in the peripheral-blood cells of 17,182 persons who were unselected for hematologic phenotypes. We looked for somatic mutations by identifying previously characterized single-nucleotide variants and small insertions or deletions in 160 genes that are recurrently mutated in hematologic cancers. The presence of mutations was analyzed for an association with hematologic phenotypes, survival, and cardiovascular events. Detectable somatic mutations were rare in persons younger than 40 years of age but rose appreciably in frequency with age. Among persons 70 to 79 years of age, 80 to 89 years of age, and 90 to 108 years of age, these clonal mutations were observed in 9.5% (219 of 2300 persons), 11.7% (37 of 317), and 18.4% (19 of 103), respectively. The majority of the variants occurred in three genes: DNMT3A, TET2, and ASXL1. The presence of a somatic mutation was associated with an increase in the risk of hematologic cancer (hazard ratio, 11.1; 95% confidence interval [CI], 3.9 to 32.6), an increase in all-cause mortality (hazard ratio, 1.4; 95% CI, 1.1 to 1.8), and increases in the risks of incident coronary heart disease (hazard ratio, 2.0; 95% CI, 1.2 to 3.4) and ischemic stroke (hazard ratio, 2.6; 95% CI, 1.4 to 4.8). Age-related clonal hematopoiesis is a common condition that is associated with increases in the risk of hematologic cancer and in all-cause mortality, with the latter possibly due to an increased risk of cardiovascular disease. (Funded by the National Institutes of Health and others.).
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            Progress and challenges in translating the biology of atherosclerosis.

            Peter Libby, Paul Ridker, Goran Hansson (2011)
            Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.
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              Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice

              José J. Fuster, Susan MacLauchlan, Maria Zuriaga … (2017)
              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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                Author and article information

                Journal
                Journal ID (nlm-ta): J Investig Med High Impact Case Rep
                Journal ID (iso-abbrev): J Investig Med High Impact Case Rep
                Journal ID (publisher-id): HIC
                Journal ID (hwp): sphic
                Title: Journal of Investigative Medicine High Impact Case Reports
                Publisher: SAGE Publications (Sage CA: Los Angeles, CA )
                ISSN (Electronic): 2324-7096
                Publication date (Electronic): 12 January 2024
                Publication date Collection: Jan-Dec 2024
                Volume: 12
                Electronic Location Identifier: 23247096231224366
                Affiliations
                [1 ]Cleveland Clinic, OH, USA
                [2 ]Cleveland Clinic Abu Dhabi, United Arab Emirates
                Author notes
                [*]Syed Bukhari, MD, Department of Cardiovascular Medicine, Section of Vascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, J 3-5, Cleveland, OH 44195, USA. Email: bukhars6@ 123456ccf.org
                Author information
                https://orcid.org/0000-0002-0244-3716
                Article
                Publisher ID: 10.1177_23247096231224366
                DOI: 10.1177/23247096231224366
                PMC ID: 10787530
                PubMed ID: 38214069
                SO-VID: eab47b0d-c967-4176-9211-f7809572cb37
                Copyright © © 2024 American Federation for Medical Research
                License:

                This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Date received : 12 October 2023
                Date revision received : 29 November 2023
                Date accepted : 15 December 2023
                Categories
                Subject: Case Report
                Custom metadata
                cover-date January-December 2024
                typesetter ts1

                Keywords: hematology oncology,radiology/imaging,tet2 mutation,recurrent atheroembolism
                Data availability:
                Keywords: hematology oncology, radiology/imaging, tet2 mutation, recurrent atheroembolism

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