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.
Bibliographical noteFunding Information:
We thank members of the Aifantis laboratory for discussions; M. Xu and F. Yang for help and advice; L. Pasqualucci (Columbia University) for control antibodies and control tissue sections for immunohistochemistry of mouse B cell lymphomas and expertise; K. Ganz, R. Flannery, D. Fu and T. Adil for help with animal husbandry and tissue collection; A. Heguy and I. Dolgalev for assistance with microarray experiments, RNA-seq and exome sequencing; the NYU Flow Cytometry facility for cell sorting; the NYU Histology Core; and E. Oricchio for assistance with analysis of data from patients with FL. Supported by the Damon Runyon Cancer Research Foundation (M.M.D.), the US National Institutes of Health (5RO1HD045022 and 5R37CA084198 for work in the laboratory of R.J.; and 1R01CA169784, 1R01CA133379, 1R01CA105129, 1R01CA149655 and 5R01CA173636 for the Aifantis laboratory), the Simons Foundation (for work in the laboratory of R.J.), the William Lawrence and Blanche Hughes Foundation, The Leukemia & Lymphoma Society (TRP#6340-11 and LLS#6373-13), The Chemotherapy Foundation, The V Foundation for Cancer Research, the Alex’s Lemonade Stand Foundation for Childhood Cancer, the St. Baldrick’s Cancer Research Foundation, the National Health and Medical Research Council (L.C.) and the Howard Hughes Medical Institute (I.A.).