TET2 deficiency reprograms the germinal center B cell epigenome and silences genes linked to lymphomagenesis
W Rosikiewicz, X Chen, PM Dominguez… - Science …, 2020 - science.org
Science advances, 2020•science.org
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 …
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 …
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-induced demethylation is markedly impaired in TET2-deficient GC B cells, suggesting that AID epigenetic effects are partially dependent on TET2. Last, we find that TET2 mutant DLBCLs also manifest the aberrant TET2-deficient GC DNA methylation signature, suggesting that this epigenetic pattern is maintained during and contributes to lymphomagenesis.
