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Cancer Discov. 2018 Oct 1. doi: 10.1158/2159-8290.CD-18-0657. [Epub ahead of print]

TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis.

Author information

1
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York.
2
INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
3
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
4
CNRS UMR8200, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
5
Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida.
6
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.
7
Department of Pathology, Laura and Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, New York.
8
Department of Lymphoma/Myeloma and Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
10
Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
11
Pathology and Laboratory Medicine Department, Weill Cornell Medicine, New York, New York.
12
INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France. amm2014@med.cornell.edu olivier.bernard@inserm.fr Said.AOUFOUCHI@gustaveroussy.fr sheng.li@jax.org rshaknovich@gmail.com.
13
CNRS UMR8200, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France. amm2014@med.cornell.edu olivier.bernard@inserm.fr Said.AOUFOUCHI@gustaveroussy.fr sheng.li@jax.org rshaknovich@gmail.com.
14
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut. amm2014@med.cornell.edu olivier.bernard@inserm.fr Said.AOUFOUCHI@gustaveroussy.fr sheng.li@jax.org rshaknovich@gmail.com.
15
The Jackson Laboratory Cancer Center, Bar Harbor, Maine.
16
Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, Connecticut.
17
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York. amm2014@med.cornell.edu olivier.bernard@inserm.fr Said.AOUFOUCHI@gustaveroussy.fr sheng.li@jax.org rshaknovich@gmail.com.
18
Cancer Genetics, Inc., Rutherford, New Jersey.
#
Contributed equally

Abstract

TET2 somatic mutations occur in ∼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. Cancer Discov 8(12); 1-22. ©2018 AACR. See related commentary by Shingleton and Dave, p. 1515.

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