Journal article

TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis

Wojciech Rosikiewicz, Xiaowen Chen, Pilar M Dominguez, Hussein Ghamlouch, Said Aoufouchi, Olivier A Bernard, Ari Melnick, Sheng Li

SCIENCE ADVANCES | AMER ASSOC ADVANCEMENT SCIENCE | Published : 2020

Abstract

The TET2 DNA hydroxymethyltransferase is frequently disrupted by somatic mutations in diffuse large B cell lymphomas (DLBCLs), a tumor that originates from germinal center (GC) B cells. Here, we show that TET2 deficiency leads to DNA hypermethylation of regulatory elements in GC B cells, associated with silencing of the respective genes. This hypermethylation affects the binding of transcription factors including those involved in exit from the GC reaction and involves pathways such as B cell receptor, antigen presentation, CD40, and others. Normal GC B cells manifest a typical hypomethylation signature, which is caused by AID, the enzyme that mediates somatic hypermutation. However, AID-ind..

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Grants

Awarded by Follicular Lymphoma Consortium


Awarded by National Institute of General Medical Sciences of the NIH


Awarded by Jackson Laboratory Director's Innovation Fund


Awarded by National Cancer Institute of the NIH


Funding Acknowledgements

A.M. is funded by R35 CA220499, LLS TRP 6572-19, LLS SCOR 7012-16, the Follicular Lymphoma Consortium, Samuel Waxman Cancer Research Foundation, and the Chemotherapy Foundation. S.L. is supported by the National Institute of General Medical Sciences of the NIH under award number R35 GM133562, Leukemia Research Foundation New Investigator Grant, The Jackson Laboratory Director's Innovation Fund 19000-17-31, and The Jackson Laboratory Cancer Center New Investigator Award. Research reported in this publication was partially supported by the National Cancer Institute of the NIH under award number P30 CA034196. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. P.M.D. was supported by a Lymphoma Research Foundation Postdoctoral Fellowship.