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      Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans

      research-article
      1 , 2 , 3 , 4 , 5 , 6 , 7 , 1 , 2 , 8 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 2 , 3 , 4 , 3 , 4 , 9 , 2 , 10 , 11 , 7 , 12 , 13 , 12 , 13 , 14 , 7 , 15 , 16 , 17 , 17 , 1 , 2 , 14 , 18 , 19 , 8 , 20 , 21 , 2 , 3 , 4 , 1 , 2 , , 1 , 2 , 3 ,
      Nature Communications
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          Abstract

          Clonal hematopoiesis driven by somatic heterozygous TET2 loss is linked to malignant degeneration via consequent aberrant DNA methylation, and possibly to cardiovascular disease via increased cytokine and chemokine expression as reported in mice. Here, we discover a germline TET2 mutation in a lymphoma family. We observe neither unusual predisposition to atherosclerosis nor abnormal pro-inflammatory cytokine or chemokine expression. The latter finding is confirmed in cells from three additional unrelated TET2 germline mutation carriers. The TET2 defect elevates blood DNA methylation levels, especially at active enhancers and cell-type specific regulatory regions with binding sequences of master transcription factors involved in hematopoiesis. The regions display reduced methylation relative to all open chromatin regions in four DNMT3A germline mutation carriers, potentially due to TET2-mediated oxidation. Our findings provide insight into the interplay between epigenetic modulators and transcription factor activity in hematological neoplasia, but do not confirm the putative role of TET2 in atherosclerosis.

          Abstract

          Somatic heterozygous TET2 loss drives clonal hematopoiesis, which is linked to malignant cell degeneration and potentially cardiovascular disease. Here, the authors investigate the molecular impact of a germline TET2 mutation in a lymphoma family, finding elevated blood DNA methylation levels and no predisposition to atherosclerosis

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          Most cited references30

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          Immunogenetics. Chromatin state dynamics during blood formation.

          Chromatin modifications are crucial for development, yet little is known about their dynamics during differentiation. Hematopoiesis provides a well-defined model to study chromatin state dynamics; however, technical limitations impede profiling of homogeneous differentiation intermediates. We developed a high-sensitivity indexing-first chromatin immunoprecipitation approach to profile the dynamics of four chromatin modifications across 16 stages of hematopoietic differentiation. We identify 48,415 enhancer regions and characterize their dynamics. We find that lineage commitment involves de novo establishment of 17,035 lineage-specific enhancers. These enhancer repertoire expansions foreshadow transcriptional programs in differentiated cells. Combining our enhancer catalog with gene expression profiles, we elucidate the transcription factor network controlling chromatin dynamics and lineage specification in hematopoiesis. Together, our results provide a comprehensive model of chromatin dynamics during development. Copyright © 2014, American Association for the Advancement of Science.
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            Human Monocytes Engage an Alternative Inflammasome Pathway.

            Interleukin-1β (IL-1β) is a cytokine whose bioactivity is controlled by activation of the inflammasome. However, in response to lipopolysaccharide, human monocytes secrete IL-1β independently of classical inflammasome stimuli. Here, we report that this constituted a species-specific response that is not observed in the murine system. Indeed, in human monocytes, lipopolysaccharide triggered an "alternative inflammasome" that relied on NLRP3-ASC-caspase-1 signaling, yet was devoid of any classical inflammasome characteristics including pyroptosome formation, pyroptosis induction, and K(+) efflux dependency. Genetic dissection of the underlying signaling pathway in a monocyte transdifferentiation system revealed that alternative inflammasome activation was propagated by TLR4-TRIF-RIPK1-FADD-CASP8 signaling upstream of NLRP3. Importantly, involvement of this signaling cascade was limited to alternative inflammasome activation and did not extend to classical NLRP3 activation. Because alternative inflammasome activation embraces both sensitivity and promiscuity of TLR4, we propose a pivotal role for this signaling cascade in TLR4-driven, IL-1β-mediated immune responses and immunopathology in humans.
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              Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome

              Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in healthy older individuals, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis.
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                Author and article information

                Contributors
                outi.kilpivaara@helsinki.fi
                lauri.aaltonen@helsinki.fi , lauri.aaltonen@ki.se
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                19 March 2019
                19 March 2019
                2019
                : 10
                : 1252
                Affiliations
                [1 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Department of Medical and Clinical Genetics, , University of Helsinki, ; FI-00014 Helsinki, Finland
                [2 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Genome-Scale Biology, Research Programs Unit, , University of Helsinki, ; FI-00014 Helsinki, Finland
                [3 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Biosciences and Nutrition, , Karolinska Institutet, ; SE 171 77 Stockholm, Sweden
                [4 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Department of Medical Biochemistry and Biophysics, , Karolinska Institutet, ; SE 171 77 Stockholm, Sweden
                [5 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, Department of Clinical Genetics, , Oulu University Hospital, ; FI-90029 Oulu, Finland
                [6 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, PEDEGO Research Unit, Medical Research Center Oulu, , Oulu University Hospital and University of Oulu, ; FI-90014 Oulu, Finland
                [7 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Institute for Molecular Medicine Finland (FIMM), HiLIFE, , University of Helsinki, ; FI-00014 Helsinki, Finland
                [8 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Clinicum, , University of Helsinki, ; FI-00014 Helsinki, Finland
                [9 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, HUSLAB, , Helsinki University Hospital, ; FI-00029 Helsinki, Finland
                [10 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Cancer and Translational Medicine Research Unit, , University of Oulu, ; FI-90014 Oulu, Finland
                [11 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, Department of Clinical Genetics, , Helsinki University Hospital, ; FI-00029 Helsinki, Finland
                [12 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry, , Massachusetts General Hospital, ; Boston, 02114 MA USA
                [13 ]GRID grid.66859.34, The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, , The Broad Institute of MIT and Harvard, ; Cambridge, 02142 MA USA
                [14 ]GRID grid.410567.1, Department of Biomedicine, Experimental Hematology, , University Hospital Basel and University of Basel, ; Basel, CH-4031 Switzerland
                [15 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, Medical Research Center Oulu, , Oulu University Hospital and University of Oulu, ; FI-90014 Oulu, Finland
                [16 ]ISNI 0000 0001 0941 4873, GRID grid.10858.34, Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, , University of Oulu, ; FI-90014 Oulu, Finland
                [17 ]ISNI 0000 0004 4685 4917, GRID grid.412326.0, Research Unit of Internal Medicine, Medical Research Center Oulu, , Oulu University Hospital and University of Oulu, ; FI-90014 Oulu, Finland
                [18 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, , University of Helsinki and Helsinki University Hospital, ; FI-00029 Helsinki, Finland
                [19 ]ISNI 0000 0004 0410 2071, GRID grid.7737.4, Rare Diseases Center, Children’s Hospital, , University of Helsinki and Helsinki University Hospital, ; FI-00029 Helsinki, Finland
                [20 ]ISNI 0000 0000 9950 5666, GRID grid.15485.3d, Department of Rheumatology, , Helsinki University Hospital, ; FI-00029 Helsinki, Finland
                [21 ]ORTON Orthopaedic Hospital, FI-00280 Helsinki, Finland
                Author information
                http://orcid.org/0000-0001-5151-1220
                http://orcid.org/0000-0003-2583-0150
                http://orcid.org/0000-0003-3528-4683
                http://orcid.org/0000-0002-7754-9021
                http://orcid.org/0000-0002-8475-7187
                http://orcid.org/0000-0001-7547-0902
                Article
                9198
                10.1038/s41467-019-09198-7
                6424975
                30890702
                adfec5b0-7a5f-48d7-8535-9e515eed1d7b
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 10 December 2018
                : 25 February 2019
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