Journal
CANCER DISCOVERY
Volume 8, Issue 12, Pages 1632-1653Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-0657
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Funding
- Office of the Director of the NIH [S10OD019986]
- Lymphoma Research Foundation Postdoctoral Fellowship
- Fondation de France [00067113]
- NSF CAREER
- Starr Cancer Consortium [I6-A618, NIH1R01CA19454]
- Institut National du Cancer [2013-PLBIO-09, 2016-PLBIO-068, INCa-DGOS-INSERM 12551]
- Association Laurette Fugain
- Comite Val-d'Oise de la Ligue contre le cancer
- Leukemia Research Foundation Research Grant
- Jackson Laboratory Cancer Center New Investigator Award
- Jackson Laboratory Director's Innovation Fund
- NCI of the NIH [P30CA034196]
- Chemotherapy Foundation
- Leukemia and Lymphoma Society SCOR Grant [7012-16]
- Follicular Lymphoma Research Consortium
- Starr Cancer Consortium
- equipe labelisee Ligue Nationale Contre le Cancer
- LLS SCOR
- Hirschl Trust Award
- [R01 CA201380]
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TET2 somatic mutations occur in similar to 10% of diffuse large B-cell lymphomas (DLBCL) but are of unknown significance. Herein, we show that TET2 is required for the humoral immune response and is a DLBCL tumor suppressor. TET2 loss of function disrupts transit of B cells through germinal centers (GC), causing GC hyperplasia, impaired class switch recombination, blockade of plasma cell differentiation, and a preneoplastic phenotype. TET2 loss was linked to focal loss of enhancer hydroxymethylation and transcriptional repression of genes that mediate GC exit, such as PRDM1. Notably, these enhancers and genes are also repressed in CREBBP-mutant DLBCLs. Accordingly, TET2 mutation in patients yields a CREBBP-mutant gene-expression signature, CREBBP and TET2 mutations are generally mutually exclusive, and hydroxymethylation loss caused by TET2 deficiency impairs enhancer H3K27 acetylation. Hence, TET2 plays a critical role in the GC reaction, and its loss of function results in lymphomagenesis through failure to activate genes linked to GC exit signals. SIGNIFICANCE: We show that TET2 is required for exit of the GC, B-cell differentiation, and is a tumor suppressor for mature B cells. Loss of TET2 phenocopies CREBBP somatic mutation. These results advocate for sequencing TET2 in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors. (C) 2018 AACR.
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