TET1 is a tumor suppressor of hematopoietic malignancy

  • Nat Immunol. 2015 Jun;16(6):653-62. doi: 10.1038/ni.3148.
Luisa Cimmino  1 ,  Meelad M Dawlaty  2 ,  Delphine Ndiaye-Lobry  1 ,  Yoon Sing Yap  1 ,  Sofia Bakogianni  1 ,  Yiting Yu  3 ,  Sanchari Bhattacharyya  3 ,  Rita Shaknovich  4 ,  Huimin Geng  5 ,  Camille Lobry  1 ,  Jasper Mullenders  1 ,  Bryan King  1 ,  Thomas Trimarchi  1 ,  Beatriz Aranda-Orgilles  1 ,  Cynthia Liu  6 ,  Steven Shen  7 ,  Amit K Verma  3 ,  Rudolf Jaenisch  2 ,  Iannis Aifantis  1
Affiliations
  • 1. 1] Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York, USA. [2] NYU Cancer Institute and Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York, USA.
  • 2. 1] Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA. [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
  • 3. Department of Hemato-Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, USA.
  • 4. Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.
  • 5. Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA.
  • 6. Howard Hughes Medical Institute and Department of Pathology, NYU School of Medicine, New York, New York, USA.
  • 7. Center for Health Informatics and Bioinformatics, NYU School of Medicine, New York, New York, USA.
PMID: 25867473 DOI: 10.1038/ni.3148
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.