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

MESH: Animals MESH: CREB-Binding Protein MESH: Cell Differentiation MESH: DNA-Binding Proteins MESH: Dioxygenases MESH: Epigenesis, Genetic MESH: Gene Expression Profiling MESH: Germinal Center MESH: Hematopoietic Stem Cells MESH: Humans MESH: Hyperplasia MESH: Lymphoma, Large B-Cell, Diffuse MESH: Mice, Knockout MESH: Mice, Transgenic MESH: Mutation MESH: Plasma Cells MESH: Positive Regulatory Domain I-Binding Factor 1 MESH: Proto-Oncogene Proteins -bio]

Sujets proches En

Units of inheritance Units of heredity Lymphoma Non-Hodgkin's lymphoma Germinoblastomas Sarcoma, Germinoblastic Sarcoma, Immunoblastic Reticulolymphosarcomas Immunoblastomas Cell fate specification Cells--Specification Differentiation of cells Specification of cells Cell specification Fate specification of cells Cells--Differentiation Cells--Fate specification

Citer ce document

Pilar Dominguez et al., « TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis », HAL SHS (Sciences de l’Homme et de la Société), ID : 10.1158/2159-8290.CD-18-0657

Partage / Export

Résumé En

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

{"uri":"10670\/1.73b591d32344c924db7c03205e64dfe35899d120","titles":{"en":"TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis"},"disciplines":[{"uri":"http:\/\/aurehal.archives-ouvertes.fr\/subject\/shs.hisphilso","label":{"fr":"Histoire, Philosophie et Sociologie des sciences","es":"Historia, Filosof\u00eda y Sociolog\u00eda de las Ciencias","en":"History, Philosophy and Sociology of Sciences"}}],"creators":[{"id":"dominguez_pilar","lastname":"Dominguez"},{"id":"ghamlouch_hussein","lastname":"Ghamlouch"},{"id":"rosikiewicz_wojciech","lastname":"Rosikiewicz"},{"id":"kumar_parveen","lastname":"Kumar"},{"id":"beguelin_wendy","lastname":"B\u00e9guelin"},{"id":"fontan_lorena","lastname":"Font\u00e1n"},{"id":"rivas_martin","lastname":"Rivas"},{"id":"pawlikowska_patrycja","lastname":"Pawlikowska"},{"id":"armand_marine","lastname":"Armand"},{"id":"mouly_enguerran","lastname":"Mouly"},{"id":"torres-martin_miguel","lastname":"Torres-Martin"},{"id":"doane_ashley","lastname":"Doane"},{"id":"calvo_fernandez_maria","lastname":"Calvo Fernandez"},{"id":"durant_matt","lastname":"Durant"},{"id":"della-valle_veronique","lastname":"Della-Valle"},{"id":"teater_matt","lastname":"Teater"},{"id":"cimmino_luisa","lastname":"Cimmino"},{"id":"droin_nathalie","lastname":"Droin"},{"id":"tadros_saber","lastname":"Tadros"},{"id":"motanagh_samaneh","lastname":"Motanagh"},{"id":"shih_alan","lastname":"Shih"},{"id":"rubin_mark","lastname":"Rubin"},{"id":"tam_wayne","lastname":"Tam"},{"id":"aifantis_iannis","lastname":"Aifantis"},{"id":"levine_ross","lastname":"Levine"},{"id":"elemento_olivier","lastname":"Elemento"},{"id":"inghirami_giorgio","lastname":"Inghirami"},{"id":"green_michael","lastname":"Green"},{"id":"figueroa_maria","lastname":"Figueroa"},{"id":"bernard_olivier","lastname":"Bernard"},{"id":"aoufouchi_said","lastname":"Aoufouchi"},{"id":"li_sheng","lastname":"Li"},{"id":"shaknovich_rita","lastname":"Shaknovich"},{"id":"melnick_ari","lastname":"Melnick"}]}

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

Fiche du document

Mots-clés Und

Sujets proches En

Citer ce document

Métriques

Partage / Export

Résumé En

Par les mêmes auteurs

Sur les mêmes sujets

Sur les mêmes disciplines