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

• Published in: Nature communications Vol. 10; no. 1; p. 1252
• Main Authors: Kaasinen, Eevi, Kuismin, Outi, Rajamäki, Kristiina, Ristolainen, Heikki, Aavikko, Mervi, Kondelin, Johanna, Saarinen, Silva, Berta, Davide G., Katainen, Riku, Hirvonen, Elina A. M., Karhu, Auli, Taira, Aurora, Tanskanen, Tomas, Alkodsi, Amjad, Taipale, Minna, Morgunova, Ekaterina, Franssila, Kaarle, Lehtonen, Rainer, Mäkinen, Markus, Aittomäki, Kristiina, Palotie, Aarno, Kurki, Mitja I., Pietiläinen, Olli, Hilpert, Morgane, Saarentaus, Elmo, Niinimäki, Jaakko, Junttila, Juhani, Kaikkonen, Kari, Vahteristo, Pia, Skoda, Radek C., Seppänen, Mikko R. J., Eklund, Kari K., Taipale, Jussi, Kilpivaara, Outi, Aaltonen, Lauri A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.03.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 45/77; 45/91; 49/15; 631/208/176/1988; 692/4019/592; 692/699/1541/1990; 82/1; 82/80; Adult; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - pathology; Cardiovascular diseases; Cells, Cultured; Chemokines; Chromatin; Cytokines; Degeneration; Deoxyribonucleic acid; Dioxygenases; DNA; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA methylation; DNA Methylation - genetics; DNA Methyltransferase 3A; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Enhancers; Epigenesis, Genetic; Female; Finland; Genetic Predisposition to Disease; Germ-Line Mutation; Haploinsufficiency; Hematology; Hematopoiesis; Hematopoiesis - genetics; Hodgkin Disease - blood; Hodgkin Disease - genetics; Hodgkin Disease - pathology; Humanities and Social Sciences; Humans; Inflammation; Lymphoma; Male; Medicin och hälsovetenskap; Modulators; multidisciplinary; Mutation; Oxidation; Phenotype; Phenotypes; Primary Cell Culture; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Regulatory sequences; RNA, Small Interfering - metabolism; Science; Science (multidisciplinary); Transcription factors; Whole Genome Sequencing; Finland
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09198-7

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. 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