TET1 is a tumor suppressor of hematopoietic malignancy

Luisa Cimmino, Meelad M. Dawlaty, Delphine Ndiaye-Lobry, Yoon Sing Yap, Sofia Bakogianni, Yiting Yu, Sanchari Bhattacharyya, Rita Shaknovich, Huimin Geng, Camille Lobry, Jasper Mullenders, Bryan King, Thomas Trimarchi, Beatriz Aranda-Orgilles, Cynthia Liu, Steven Shen, Amit K. Verma, Rudolf Jaenisch, Iannis Aifantis

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)653-662
Number of pages10
JournalNature Immunology
Volume16
Issue number6
DOIs
StatePublished - May 19 2015

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Cimmino, L., Dawlaty, M. M., Ndiaye-Lobry, D., Yap, Y. S., Bakogianni, S., Yu, Y., Bhattacharyya, S., Shaknovich, R., Geng, H., Lobry, C., Mullenders, J., King, B., Trimarchi, T., Aranda-Orgilles, B., Liu, C., Shen, S., Verma, A. K., Jaenisch, R., & Aifantis, I. (2015). TET1 is a tumor suppressor of hematopoietic malignancy. Nature Immunology, 16(6), 653-662. https://doi.org/10.1038/ni.3148