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

Domínguez, Pilar M.; Ghamlouch, Hussein; Rosikiewicz, Wojciech; Kumar, Parveen; Béguelin, Wendy; Fontán, Lorena; Rivas, Martín A.; Pawlikowska, Patrycja; Armand, Marine; Mouly, Enguerran; Torres‐Martín, Miguel; Doane, Ashley S.; Fernández, María Teresa Calvo; Durant, Matt; Della-Valle, Véronique; 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, María E.; Bernard, Olivier A.; Aoufouchi, Saïd; Li, Sheng; Shaknovich, Rita; Melnick, Ari

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

Cited by 133 publications

(172 citation statements)

References 74 publications

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“…This is consistent with a comparable fraction of apoptotic cells (Fig. This is in line with Dominguez et al [46] who propose that low TET2 levels, such as in patients with clonal hematopoiesis of indeterminate potential that present with TET2 loss-of-function mutations [47], prevent terminal differentiation hence facilitating B lymphomagenesis. To confirm in an independent culture system that TET-deficiency does not impact the proliferation of activated B cells, na€ ıve B cells were labelled with a proliferation-tracking dye and stimulated with aCD40/IL-4/IL-21 or LPS/IL-4/IL-5.…”

Section: Resultssupporting

confidence: 90%

“…2E). TET2 might serve a dominant role, as it was shown to cause the demethylation of intronic CpGs in the Prdm1 locus encoding BLIMP-1 [46], a key transcriptional repressor for plasmacytic differentiation. Whereas TET2 was initially down-regulated and moderately up-regulated in division cycles 5-6, down-regulation of TET3 was only apparent once the cells had divided > 4 times.…”

Section: Resultsmentioning

confidence: 99%

“…In GC B cells, mutagenesis is largely a consequence of AID activity [56]. Up to 10% of human DLBCL exhibit TET2 loss-of-function mutations, and these mutations usually occur mutually exclusive with mutations in regulators of TET function [46,60]. This suggests that TET proteins may at least partially exert their tumour suppressor activity in GC B cell-derived lymphomas by orchestrating the mutagenic potential of AID.…”

Section: Loss Of Tet Function Does Not Impair Affinity Maturation Butmentioning

confidence: 99%

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TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

et al. 2019

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Upon activation by antigen, B cells form germinal centres where they clonally expand and introduce affinity‐enhancing mutations into their B‐cell receptor genes. Somatic mutagenesis and class switch recombination (CSR) in germinal centre B cells are initiated by the activation‐induced cytidine deaminase (AID). Upon germinal centre exit, B cells differentiate into antibody‐secreting plasma cells. Germinal centre maintenance and terminal fate choice require transcriptional reprogramming that associates with a substantial reconfiguration of DNA methylation patterns. Here we examine the role of ten‐eleven‐translocation (TET) proteins, enzymes that facilitate DNA demethylation and promote a permissive chromatin state by oxidizing 5‐methylcytosine, in antibody‐mediated immunity. Using a conditional gene ablation strategy, we show that TET2 and TET3 guide the transition of germinal centre B cells to antibody‐secreting plasma cells. Optimal AID expression requires TET function, and TET2 and TET3 double‐deficient germinal centre B cells show defects in CSR. However, TET2/TET3 double‐deficiency does not prevent the generation and selection of high‐affinity germinal centre B cells. Rather, combined TET2 and TET3 loss‐of‐function in germinal centre B cells favours C‐to‐T and G‐to‐A transition mutagenesis, a finding that may be of significance for understanding the aetiology of B‐cell lymphomas evolving in conditions of reduced TET function.

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Section: Resultssupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Loss Of Tet Function Does Not Impair Affinity Maturation Butmentioning

confidence: 99%

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TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

et al. 2019

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“…There, the duration of their interaction depends on their specificity and affinity for the encountered antigen. [38][39][40] 37 Along these lines, genetic lesions that occur prior to the GC reaction, such as those affecting TET2 (arising in hematopoietic stem cells) or BCL2 (in pre-B cells), may confer preferential initial expansion and survival of mutant cells, resulting in an expanded population of GC B cells at risk for acquiring a "second hit."…”

Section: Gc Entrymentioning

confidence: 99%

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Mlynarczyk

Fontán

Melnick

2019

Immunological Reviews

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133

142

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Summary One of the unusual features of germinal center (GC) B cells is that they manifest many hallmarks of cancer cells. Accordingly, most B‐cell neoplasms originate from the GC reaction, and characteristically display abundant point mutations, structural genomic lesions, and clonal diversity from the genetic and epigenetic standpoints. The dominant biological theme of GC‐derived lymphomas is mutation of genes involved in epigenetic regulation and immune receptor signaling, which come into play at critical transitional stages of the GC reaction. Hence, mechanistic studies of these mutations reveal fundamental insight into the biology of the normal and malignant GC B cell. The BCL6 transcription factor plays a central role in establishing the GC phenotype in B cells, and most lymphomas are dependent on BCL6 to maintain survival, proliferation, and perhaps immune evasion. Many lymphoma mutations have the commonality of enhancing the oncogenic functions of BCL6, or overcoming some of its tumor suppressive effects. Herein, we discuss how unique features of the GC reaction create vulnerabilities that select for particular lymphoma mutations. We examine the interplay between epigenetic programming, metabolism, signaling, and immune regulatory mechanisms in lymphoma, and discuss how these are leading to novel precision therapy strategies to treat lymphoma patients.

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“…Analogous to FL, a major, previously unappreciated program dysregulated by genetic lesions in DLBCL is represented by epigenetic remodeling, exemplified by genes encoding for histone/chromatin modifiers, 83,134,157 most commonly the methyltransferase KMT2D (30% of cases), 134 the acetyltransferases CREBBP and EP300 (20% and 5% of cases, respectively), 83 and the polycomb-group oncogene EZH2 (20% of patients), 133 with linker histones, ARID1A, and TET2 163 accounting for a small fractions of cases. Although some of these lesions tend to preferentially (CREBBP/EP300) or even exclusively (EZH2) segregate with GCB-DLBCL, being enriched in the EZB or C3 genetic cluster, epigenetic perturbation conceivably plays a pervasive role in all disease subgroups, possibly as facilitator during the initial stages of the malignant transformation process.…”

Section: Epigenetic Remodelingmentioning

confidence: 99%

Molecular pathogenesis of germinal center‐derived B cell lymphomas

Pasqualucci

2019

Immunological Reviews

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Summary B cell lymphomas comprise a heterogeneous group of genetically, biologically, and clinically distinct neoplasms that, in most cases, originate from the clonal expansion of B cells in the germinal center (GC). In recent years, the advent of novel genomics technologies has revolutionized our understanding of the molecular pathogenesis of lymphoid malignancies as a multistep process that requires the progressive accumulation of multiple genetic and epigenetic alterations. A common theme that emerged from these studies is the ability of lymphoma cells to co‐opt the same biological programs and signal transduction networks that operate during the normal GC reaction, and misuse them for their own survival advantage. This review summarizes recent progress in the understanding of the genetic and epigenetic mechanisms that drive the malignant transformation of GC B cells. These insights provide a conceptual framework for the identification of cellular pathways that may be explored for precision medicine approaches.

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

Cited by 133 publications

References 74 publications

TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

TET enzymes control antibody production and shape the mutational landscape in germinal centre B cells

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Molecular pathogenesis of germinal center‐derived B cell lymphomas

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