TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis.
Cancer Discov 2018 Dec; 8(12):1632-1653
CA034196, Leukemia Research Foundation, The Jackson Laboratory Cancer Center New Investigator Award, The Jackson Laboratory Director's Innovation Fund
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.
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; and Melnick, Ari M, "TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis." (2018). Faculty Research 2018. 242.