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

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, Aurora Taira, Tomas Tanskanen, Amjad Alkodsi, Minna Taipale, Ekaterina Morgunova, Kaarle Franssila, Rainer Lehtonen, Markus Mäkinen, Kristiina Aittomäki, Aarno Palotie, Mitja I. Kurki, Olli Pietiläinen, Morgane Hilpert, Elmo Saarentaus, Jaakko Niinimäki, Juhani Junttila, Kari Kaikkonen, Pia Vahteristo, Radek C. Skoda, Mikko R. J. Seppänen, Kari K. Eklund, Jussi Taipale, Outi Kilpivaara () and Lauri A. Aaltonen ()
Additional contact information
Eevi Kaasinen: University of Helsinki
Outi Kuismin: Oulu University Hospital
Kristiina Rajamäki: University of Helsinki
Heikki Ristolainen: University of Helsinki
Mervi Aavikko: University of Helsinki
Johanna Kondelin: University of Helsinki
Silva Saarinen: University of Helsinki
Davide G. Berta: University of Helsinki
Riku Katainen: University of Helsinki
Elina A. M. Hirvonen: University of Helsinki
Auli Karhu: University of Helsinki
Aurora Taira: University of Helsinki
Tomas Tanskanen: University of Helsinki
Amjad Alkodsi: University of Helsinki
Minna Taipale: Karolinska Institutet
Ekaterina Morgunova: 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
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
Juhani Junttila: Oulu University Hospital and University of Oulu
Kari Kaikkonen: Oulu University Hospital and University of Oulu
Pia Vahteristo: University of Helsinki
Radek C. Skoda: University Hospital Basel and University of Basel
Mikko R. J. Seppänen: University of Helsinki and Helsinki University Hospital
Kari K. Eklund: University of Helsinki
Jussi Taipale: University of Helsinki
Outi Kilpivaara: University of Helsinki
Lauri A. Aaltonen: University of Helsinki

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09198-7

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DOI: 10.1038/s41467-019-09198-7

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