TET1 is a tumor suppressor of hematopoietic malignancy

• DOI: 10.1038/ni.3148
• Publication Date: 2015-04-13T15:45:42Z
• Authors: Luisa Cimmino; Meelad M Dawlaty; Delphine Ndiaye-L...; Yoon Sing Yap; Sofia Bakogianni; Yiting Yu; Sanchari Bhattach...; Rita Shaknovich; Huimin Geng; Camille Lobry; Jasper Mullenders; Bryan King; Thomas Trimarchi; Beatriz Aranda-Or...; Cynthia Liu; Steven Shen; Amit K Verma; Rudolf Jaenisch; Iannis Aifantis
• Keywords: B-Lymphocytes; Lymphoma, B-Cell; DNA Repair; Gene Expression Profiling; Tumor Suppressor Proteins; Cell Differentiation; DNA Methylation; Epigenesis, Genetic; DNA-Binding Proteins; Cytosine; Mice; Chromosomal Instability; Proto-Oncogene Proteins; Mutation; 5-Methylcytosine; Animals; Humans; Cell Lineage; Exome; Embryonic Stem Cells

The methylcytosine dioxygenase TET1 ('ten-eleven translocation 1') is an important regulator of 5-hydroxymethylcytosine (5hmC) in embryonic stem cells. The diminished expression of TET proteins and loss of 5hmC in many tumors suggests a critical role for the maintenance of this epigenetic modification. Here we found that deletion of Tet1 promoted the development of B cell lymphoma in mice. TET1 was required for maintenance of the normal abundance and distribution of 5hmC, which prevented hypermethylation of DNA, and for regulation of the B cell lineage and of genes encoding molecules involved in chromosome maintenance and DNA repair. Whole-exome sequencing of TET1-deficient tumors revealed mutations frequently found in non-Hodgkin B cell lymphoma (B-NHL), in which TET1 was hypermethylated and transcriptionally silenced. Our findings provide in vivo evidence of a function for TET1 as a tumor suppressor of hematopoietic malignancy.