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

Pilar M Dominguez; Hussein Ghamlouch; Wojciech Rosikiewicz; Parveen Kumar; Wendy Béguelin; Lorena Fontán; Martín A Rivas; Patrycja Pawlikowska; Marine Armand; Enguerran Mouly; Miguel Torres-Martin; Ashley S Doane; María T Calvo Fernandez; Matt Durant; Veronique Della-Valle; Matt Teater; Luisa Cimmino; Nathalie Droin; Saber Tadros; Samaneh Motanagh; Alan H Shih; Mark A Rubin; Wayne Tam; Iannis Aifantis; Ross L Levine; Olivier Elemento; Giorgio Inghirami; Michael R Green; Maria E Figueroa; Olivier A Bernard; Said Aoufouchi; Sheng Li; Rita Shaknovich; Ari M Melnick

doi:10.1158/2159-8290.CD-18-0657

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

Journal article

Open access

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

Pilar M Dominguez, Hussein Ghamlouch, Wojciech Rosikiewicz, Parveen Kumar, Wendy Béguelin, Lorena Fontán, Martín A Rivas, Patrycja Pawlikowska, Marine Armand, Enguerran Mouly, …

Cancer discovery, Vol.8(12), pp.1632-1653

2018-12

DOI: https://doi.org/10.1158/2159-8290.CD-18-0657

PMCID: PMC6279514

PMID: 30274972

Abstract

Positive Regulatory Domain I-Binding Factor 1 - genetics

Humans

Hyperplasia

Lymphoma, Large B-Cell, Diffuse - metabolism

Plasma Cells - pathology

CREB-Binding Protein - genetics

DNA-Binding Proteins - metabolism

CREB-Binding Protein - metabolism

Cell Differentiation - genetics

Plasma Cells - metabolism

Proto-Oncogene Proteins - metabolism

Lymphoma, Large B-Cell, Diffuse - pathology

Gene Expression Profiling - methods

Mice, Transgenic

Positive Regulatory Domain I-Binding Factor 1 - metabolism

Proto-Oncogene Proteins - genetics

Hematopoietic Stem Cells - metabolism

Germinal Center - pathology

DNA-Binding Proteins - genetics

Mice, Knockout

Animals

Germinal Center - metabolism

Epigenesis, Genetic - genetics

Mutation

Lymphoma, Large B-Cell, Diffuse - genetics

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 -mutant DLBCLs. Accordingly, mutation in patients yields a -mutant gene-expression signature, and 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 somatic mutation. These results advocate for sequencing in patients with lymphoma and for the testing of epigenetic therapies to treat these tumors. . .

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.54 Molecular & Cell Biology - Genetics; 1.54.100 DNA Methylation
Web Of Science research areas: Oncology
ESI research areas: Clinical Medicine

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Title: TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis
Creators: Pilar M Dominguez - Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
Hussein Ghamlouch - INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Wojciech Rosikiewicz - The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
Parveen Kumar - The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
Wendy Béguelin - Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
Lorena Fontán - Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
Martín A Rivas - Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
Patrycja Pawlikowska - CNRS UMR8200, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Marine Armand - CNRS UMR8200, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Enguerran Mouly - INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Miguel Torres-Martin - Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida
Ashley S Doane - Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York
María T Calvo Fernandez - Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
Matt Durant - Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, New York
Veronique Della-Valle - INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Matt Teater - Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York
Luisa Cimmino - 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
Nathalie Droin - INSERM U1170, équipe labelisée Ligue Nationale Contre le Cancer, Gustave Roussy, Université Paris-Saclay, Villejuif, France
Saber Tadros - Department of Lymphoma/Myeloma and Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Samaneh Motanagh - Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
Alan H Shih - Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York
Mark A Rubin - Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
Wayne Tam - Pathology and Laboratory Medicine Department, Weill Cornell Medicine, New York, New York
Iannis Aifantis - 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
Ross L Levine - Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York
Olivier Elemento - Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York
Giorgio Inghirami - Pathology and Laboratory Medicine Department, Weill Cornell Medicine, New York, New York
Michael R Green - Department of Lymphoma/Myeloma and Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Maria E Figueroa - Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, Florida
Olivier A Bernard - 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
Said Aoufouchi - 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
Sheng Li - Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, Connecticut
Rita Shaknovich - Cancer Genetics, Inc., Rutherford, New Jersey
Ari M Melnick - 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
Publication Details: Cancer discovery, Vol.8(12), pp.1632-1653
Publisher: United States
Grant note: R01 CA201380 / NCI NIH HHS K08 CA181507 / NCI NIH HHS P30 CA034196 / NCI NIH HHS R35 CA220499 / NCI NIH HHS S10 OD019986 / NIH HHS P30 CA008748 / NCI NIH HHS R01 CA187109 / NCI NIH HHS
Academic Unit: Miller School of Medicine; Biochemistry & Molecular Biology Research; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation)
Language: English
Resource Type: Journal article
PMID: 30274972
PMCID: PMC6279514
Record Identifier: 991031575957302976