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

Author

Listed:
  • Eevi Kaasinen

    (University of Helsinki
    University of Helsinki
    Karolinska Institutet
    Karolinska Institutet)

  • Outi Kuismin

    (Oulu University Hospital
    Oulu University Hospital and University of Oulu
    University of Helsinki)

  • Kristiina Rajamäki

    (University of Helsinki
    University of Helsinki
    University of Helsinki)

  • Heikki Ristolainen

    (University of Helsinki
    University of Helsinki)

  • Mervi Aavikko

    (University of Helsinki
    University of Helsinki)

  • Johanna Kondelin

    (University of Helsinki
    University of Helsinki)

  • Silva Saarinen

    (University of Helsinki
    University of Helsinki)

  • Davide G. Berta

    (University of Helsinki
    University of Helsinki)

  • Riku Katainen

    (University of Helsinki
    University of Helsinki)

  • Elina A. M. Hirvonen

    (University of Helsinki
    University of Helsinki)

  • Auli Karhu

    (University of Helsinki
    University of Helsinki)

  • Aurora Taira

    (University of Helsinki
    University of Helsinki)

  • Tomas Tanskanen

    (University of Helsinki
    University of Helsinki)

  • Amjad Alkodsi

    (University of Helsinki)

  • Minna Taipale

    (Karolinska Institutet
    Karolinska Institutet)

  • Ekaterina Morgunova

    (Karolinska Institutet
    Karolinska Institutet)

  • Kaarle Franssila

    (Helsinki University Hospital)

  • Rainer Lehtonen

    (University of Helsinki)

  • Markus Mäkinen

    (University of Oulu)

  • Kristiina Aittomäki

    (Helsinki University Hospital)

  • Aarno Palotie

    (University of Helsinki
    Massachusetts General Hospital
    The Broad Institute of MIT and Harvard)

  • Mitja I. Kurki

    (Massachusetts General Hospital)

  • Olli Pietiläinen

    (The Broad Institute of MIT and Harvard)

  • Morgane Hilpert

    (University Hospital Basel and University of Basel)

  • Elmo Saarentaus

    (University of Helsinki)

  • Jaakko Niinimäki

    (Oulu University Hospital and University of Oulu
    University of Oulu)

  • Juhani Junttila

    (Oulu University Hospital and University of Oulu)

  • Kari Kaikkonen

    (Oulu University Hospital and University of Oulu)

  • Pia Vahteristo

    (University of Helsinki
    University of Helsinki)

  • Radek C. Skoda

    (University Hospital Basel and University of Basel)

  • Mikko R. J. Seppänen

    (University of Helsinki and Helsinki University Hospital
    University of Helsinki and Helsinki University Hospital)

  • Kari K. Eklund

    (University of Helsinki
    Helsinki University Hospital
    ORTON Orthopaedic Hospital)

  • Jussi Taipale

    (University of Helsinki
    Karolinska Institutet
    Karolinska Institutet)

  • Outi Kilpivaara

    (University of Helsinki
    University of Helsinki)

  • Lauri A. Aaltonen

    (University of Helsinki
    University of Helsinki
    Karolinska Institutet)

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.

Suggested Citation

  • Eevi Kaasinen & Outi Kuismin & Kristiina Rajamäki & Heikki Ristolainen & Mervi Aavikko & Johanna Kondelin & Silva Saarinen & Davide G. Berta & Riku Katainen & Elina A. M. Hirvonen & Auli Karhu & Auror, 2019. "Impact of constitutional TET2 haploinsufficiency on molecular and clinical phenotype in humans," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09198-7
    DOI: 10.1038/s41467-019-09198-7
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    Cited by:

    1. Giulia Schiroli & Vinay Kartha & Fabiana M. Duarte & Trine A. Kristiansen & Christina Mayerhofer & Rojesh Shrestha & Andrew Earl & Yan Hu & Tristan Tay & Catherine Rhee & Jason D. Buenrostro & David T, 2024. "Cell of origin epigenetic priming determines susceptibility to Tet2 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Morten Tulstrup & Mette Soerensen & Jakob Werner Hansen & Linn Gillberg & Maria Needhamsen & Katja Kaastrup & Kristian Helin & Kaare Christensen & Joachim Weischenfeldt & Kirsten Grønbæk, 2021. "TET2 mutations are associated with hypermethylation at key regulatory enhancers in normal and malignant hematopoiesis," Nature Communications, Nature, vol. 12(1), pages 1-10, December.

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