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

Dominguez, Pilar M., Ghamlouch, Hussein, Rosikiewicz, Wojciech, Kumar, Parveen, Béguelin, Wendy, Fontán, Lorena, Rivas, Martín A., Pawlikowska, Patrycja, Armand, Marine, Mouly, Enguerran, Torres-Martin, Miguel, Doane, Ashley S., Calvo Fernandez, María T., Durant, Matt, Della-Valle, Veronique, Teater, Matt, Cimmino, Luisa, Droin, Nathalie, Tadros, Saber, Motanagh, Samaneh, Shih, Alan H., Rubin, Mark A., Tam, Wayne, Aifantis, Iannis, Levine, Ross L., Elemento, Olivier, Inghirami, Giorgio, Green, Michael R., Figueroa, Maria E., Bernard, Olivier A., Aoufouchi, Said, Li, Sheng, Shaknovich, Rita, Melnick, Ari M.·2018·Cancer Discovery
DOI 10.1158/2159-8290.cd-18-0657PMC PMC6279514
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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. See related commentary by Shingleton and Dave, p. 1515. This article is highlighted in the In This Issue feature, p. 1494

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Cited by

Metadata

Authors
Dominguez, P. M., Ghamlouch, H., Rosikiewicz, W., Kumar, P., Béguelin, W., Fontán, L., Rivas, M. A., Pawlikowska, P., Armand, M., Mouly, E., Torres-Martin, M., Doane, A. S., Calvo Fernandez, M. T., Durant, M., Della-Valle, V., Teater, M., Cimmino, L., Droin, N., Tadros, S., Motanagh, S., Shih, A. H., Rubin, M. A., Tam, W., Aifantis, I., Levine, R. L., Elemento, O., Inghirami, G., Green, M. R., Figueroa, M. E., Bernard, O. A., Aoufouchi, S., Li, S., Shaknovich, R., & Melnick, A. M.
Affiliations
  • 1Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York.
  • 2INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • 3The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
  • 4CNRS UMR8200, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
  • 5Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida.
  • 7Department 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.
  • 8Department of Lymphoma/Myeloma and Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 9Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York.
  • 10Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.
  • 11Pathology and Laboratory Medicine Department, Weill Cornell Medicine, New York, New York.
  • 6Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2018-12-01
Volume
8
Issue
12
Pages
1632-1653
ISSN
  • 2159-8274
  • 2159-8290
DOI
10.1158/2159-8290.cd-18-0657
PMC
PMC6279514
Cited by
178
References
12
Language
en
Funders
  • Leukemia and Lymphoma Society (LLS) (7012-16)
  • Institut National Du Cancer (INCa) (INCa-DGOS-INSERM 12551, 2013-PLBIO-09, 2016-PLBIO-068)
  • Association Laurette Fugain (Laurette Fugain)
  • Equipe labelisee Ligue Nationale Contre le Cancer
  • Starr Cancer Consortium (I6-A618)
  • HHS | National Institutes of Health (NIH) (1R01CA19454, R01 CA201380)
  • National Science Foundation (NSF)
  • Lymphoma Research Foundation (LRF)
  • Fondation de France (00067113)
  • Comite Val-d'Oise de la Ligue contre le cancer
  • The Chemotherapy Foundation
  • The Follicular Lymphoma research Foundation
  • The Jackson Laboratory Cancer Center New Investigator Award (P30CA034196)
  • The Jackson Laboratory Director's Innovation Fund (JAX-DIF 19000-17-13)
  • Leukemia Research Foundation (LRF)

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