Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans.
Eevi Kaasinen,Outi Kuismin,Outi Kuismin,Kristiina Rajamäki,Heikki Ristolainen,Mervi Aavikko,Johanna Kondelin,Silva Saarinen,Davide G. Berta,Riku Katainen,Elina A. M. Hirvonen,Auli Karhu,Aurora Taira,Tomas Tanskanen,Amjad Alkodsi,Minna Taipale,Ekaterina Morgunova,Kaarle Franssila,Rainer Lehtonen,Markus J. Mäkinen,Kristiina Aittomäki,Aarno Palotie,Aarno Palotie,Aarno Palotie,Mitja I. Kurki,Olli Pietilainen,Morgane Hilpert,Elmo Saarentaus,Jaakko Niinimäki,Jaakko Niinimäki,Juhani Junttila,Kari Kaikkonen,Pia Vahteristo,Radek C. Skoda,Mikko Seppänen,Kari K. Eklund,Jussi Taipale,Jussi Taipale,Outi Kilpivaara,Lauri A. Aaltonen,Lauri A. Aaltonen +40 more
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TLDR
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:
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.read more
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International Consensus Classification of Myeloid Neoplasms and Acute Leukemia: Integrating Morphological, Clinical, and Genomic Data.
Daniel A. Arber,Attilio Orazi,Robert P. Hasserjian,Michael Horowitz,Katherine R. Calvo,Hans Michael Kvasnicka,Sa A. Wang,Adam Bagg,Tiziano Barbui,Susan Branford,Carlos E. Bueso-Ramos,Jorge E. Cortes,Paola Dal Cin,Courtney D. DiNardo,Hervé Dombret,Eric J. Duncavage,Benjamin L. Ebert,Elihu H. Estey,Fabio Facchetti,Kathryn Foucar,Naseema Gangat,Umberto Gianelli,Lucy A. Godley,Nicola Goekbuget,Jason Gotlib,Eva Hellström-Lindberg,Gabriela S. Hobbs,Roald Hoffmann,Elias Jabbour,Jean-Jacques Kiladjian,Richard A. Larson,Michelle M. Le Beau,Mignon L. Loh,Bob Löwenberg,Elizabeth Macintyre,Luca Malcovati,Charles G. Mullighan,Charlotte M. Niemeyer,Olatoyosi Odenike,Seishi Ogawa,Alberto Orfao,Elli Papaemmanuil,Francesco Passamonti,Kimmo Porkka,C H Pui,Jerald P. Radich,Andreas Reiter,María Rozman,Martina Rudelius,Michael R. Savona,Charles A. Schiffer,Annette Schmitt-Graeff,Akiko Shimamura,Jorge Sierra,Wendy Stock,Richard Stone,Martin S. Tallman,Juergen Thiele,Hwei-Fang Tien,Alexandar Tzankov,Alessandro M. Vannucchi,Paresh Vyas,Andrew H. Wei,Olga Weinberg,Agnieszka Wierzbowska,Mario Cazzola,Hartmut Döhner,Ayalew Tefferi +67 more
TL;DR: The authors, a group with expertise in the clinical, pathologic and genetic aspects of these disorders, developed the International Consensus Classification (ICC), aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
Journal ArticleDOI
Clonal hematopoiesis and nonhematologic disorders.
TL;DR: Recent studies linking clonal hematopoiesis to altered immune function, inflammation, and non-malignant diseases of aging are reviewed.
Journal ArticleDOI
Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection.
TL;DR: In this paper, major sources of systemic inflammation act on and subsequently shape HSC fate and function, highlighting how lifelong inflammatory exposure contributes to HSC inflamm-aging and selection of premalignant HSC clones.
Journal ArticleDOI
Clonal hematopoiesis and inflammation: Partners in leukemogenesis and comorbidity
TL;DR: A growing body of evidence, primarily from studies involving Tet2-knockout and stem cell transplant models of CH, suggest that dysregulated inflammation contributes to clonal expansion and associated comorbidities.
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Clinical approach to the inflammatory etiology of cardiovascular diseases.
Massimiliano Ruscica,Alberto Corsini,Nicola Ferri,Maciej Banach,Maciej Banach,Maciej Banach,Cesare R. Sirtori +6 more
TL;DR: The inflammation-based approach to arterial disease has considerably gained from an improved understanding of the clinical diagnostic strategy and from a better knowledge on the mode of action of numerous agents, including nutraceuticals.
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