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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
Cancer discovery, 12/2018, Volume: 8, Issue: 12Journal Article
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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