TitleTET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis.
Publication TypeJournal Article
Year of Publication2018
AuthorsDominguez, Pilar M., Ghamlouch Hussein, Rosikiewicz Wojciech, Kumar Parveen, Béguelin Wendy, Fontan Lorena, Rivas Martín A., Pawlikowska Patrycja, Armand Marine, Mouly Enguerran, Torres-Martin Miguel, Doane Ashley S., Fernández María T. Calvo, 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.
JournalCancer Discov
Date Published2018 Dec
KeywordsAnimals, Cell Differentiation, CREB-Binding Protein, Dioxygenases, DNA-Binding Proteins, Epigenesis, Genetic, Gene Expression Profiling, Germinal Center, Hematopoietic Stem Cells, Humans, Hyperplasia, Lymphoma, Large B-Cell, Diffuse, Mice, Knockout, Mice, Transgenic, Mutation, Plasma Cells, Positive Regulatory Domain I-Binding Factor 1, Proto-Oncogene Proteins

<p> 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...</p>

Alternate JournalCancer Discov
PubMed ID30274972
PubMed Central IDPMC6279514
Grant ListR35 CA220499 / CA / NCI NIH HHS / United States
R01 CA187109 / CA / NCI NIH HHS / United States
P30 CA034196 / CA / NCI NIH HHS / United States
R01 CA201380 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
K08 CA181507 / CA / NCI NIH HHS / United States
S10 OD019986 / OD / NIH HHS / United States