B-cell tumor development in Tet2-deficient mice

Mouly, Enguerran; Ghamlouch, Hussein; Scourzic, Laurianne; Quivoron, Cyril; Roos‐Weil, Damien; Pawlikowska, Patrycja; Saada, Véronique; Diop, M’Boyba; Lopez, Cécile K.; Fontenay, Michaëla; Dessen, Philippe; Touw, Ivo P.; Mercher, Thomas; Aoufouchi, Saïd; Bernard, Olivier A.

doi:10.1182/bloodadvances.2017014118

Cited by 41 publications

(51 citation statements)

References 49 publications

(63 reference statements)

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“…In GC B cells, mutagenesis is largely a consequence of AID activity [56]. In accordance with our results, B-cellspecific Tet2-deficiency promoted age-dependent transformation in a fraction of mice, an outcome that strictly required AID and involved a bias towards Gto-A and C-to-T mutations in the established tumours [38]. 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 Butsupporting

confidence: 90%

“…We found that Cg1-Cre;Tet2 F/F ;Tet3 F/F GC B cells carried slightly less somatic mutations per V H 186.2 sequence (Fig. In accordance with our results, B-cellspecific Tet2-deficiency promoted age-dependent transformation in a fraction of mice, an outcome that strictly required AID and involved a bias towards Gto-A and C-to-T mutations in the established tumours [38]. Strikingly, however, V H 186.2 mutations in TET-deficient GC B cells exhibited C-to-T and G-to-A transition mutation biases (Fig.…”

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

confidence: 90%

“…TET2 and TET3 are expressed throughout B-cell development and terminal differentiation Human and mouse B cells express TET2 and TET3, whereas TET1 is barely detectable throughout development and upon activation [37][38][39][40]. To analyse the relative mRNA expression of TET2 and TET3 in cell populations spanning the entire B-cell lineage, we FACS-sorted developing and mature na€ ıve B-cell subsets from unchallenged wild-type mice and antigen-experienced B cells from mice that were immunized with sheep red blood cells (RBC), and performed quantitative real-time PCR (qRT-PCR).…”

Section: Resultsmentioning

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: Loss Of Tet Function Does Not Impair Affinity Maturation Butsupporting

confidence: 90%

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

confidence: 90%

Section: Resultsmentioning

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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“…Their data confirmed that TET2 deficiency tends to mature B-cell malignancies, and its development may be due in part to cumulative mutations and BCR-mediated signaling. 20 However, our study did not find an association between insufficient expression of TET2 and BCR-ABL1 and KMT2A-AFF1 abnormalities.…”

Section: Discussioncontrasting

confidence: 88%

Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome

Zhang

Weng

Chen

et al. 2019

Int J Lab Hematology

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Introduction TET2, a member of the Ten‐Eleven translocation gene family, catalyzes the conversion of 5‐methylcytosine to 5‐hydroxymethylcytosine in DNA. Low expression of TET2 has been reported as a prognostic factor for several types of malignancies in adult patients. However, there have been few data on the effect of TET2 mRNA level on the prognosis of children with ALL so far. Methods In this study, TET2 expression of samples cryopreserved in the liquid nitrogen from January 1, 2007 through December 31, 2011 was retrospectively analyzed in 136 newly diagnosed ALL patients by real‐time polymerase chain reaction (PCR) assay. The patients' samples were divided into two groups by the median value of patients group and divided into TET2 low and TET2 high groups. Results A total of 136 childhood ALL patients demonstrated lower TET2 expression than control group (P = .038). TET2 mRNA expression levels were correlated with the disease status. In addition, patients with low TET2 expression had lower platelet counts and lower CR rates. Survival analysis showed that low TET2 expression in children with ALL was associated with lower 5‐year overall survival (OS) (63% vs 88%, P = .011) and event‐free survival (EFS) (60% vs 85%, P = .003). Multivariate analysis revealed that low TET2 expression was an independent poor prognostic factor of OS and EFS. Conclusion Low expression of TET2 in children with ALL is associated with poor prognosis and can be used as a molecular prognostic marker for risk group stratification.

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“…Mutant mice in this pure C57BL/6 J background were housed in the animal facility of the Gustave Roussy Institute (SCEA, Gustave Roussy, Villejuif, France), crossed with WT C57BL/6 J mice and agematched animals of selected genotypes were sacrificed at the indicated times. Bone marrow transplantation were performed as described 24,25 . Animal experiments were conducted in compliance with the Gustave Roussy Institutional guidelines and authorized by the Direction Départementale des Services Vétérinaires du Val de Marne.…”

Section: Micementioning

confidence: 99%

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

et al. 2020

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Aberrant NF-κB activation is a hallmark of most B-cell malignancies. Recurrent inactivating somatic mutations in the NFKBIE gene, which encodes IκBε, an inhibitor of NF-κB-inducible activity, are reported in several B-cell malignancies with highest frequencies in chronic lymphocytic leukemia and primary mediastinal B-cell lymphoma, and account for a fraction of NF-κB pathway activation. The impact of NFKBIE deficiency on B-cell development and function remains, however, largely unknown. Here, we show that Nfkbie-deficient mice exhibit an amplification of marginal zone B cells and an expansion of B1 B-cell subsets. In germinal center (GC)-dependent immune response, Nfkbie deficiency triggers expansion of GC B-cells through increasing cell proliferation in a B-cell autonomous manner. We also show that Nfkbie deficiency results in hyperproliferation of a B1 B-cell subset and leads to increased NF-κB activation in these cells upon Toll-like receptor stimulation. Nfkbie deficiency cooperates with mutant MYD88 signaling and enhances B-cell proliferation in vitro. In aged mice, Nfkbie absence drives the development of an oligoclonal indolent B-cell lymphoproliferative disorders, resembling monoclonal B-cell lymphocytosis. Collectively, these findings shed light on an essential role of IκBε in finely tuning B-cell development and function.

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B-cell tumor development in Tet2-deficient mice

Cited by 41 publications

References 49 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

Low expression of TET2 gene in pediatric acute lymphoblastic leukemia is associated with poor clinical outcome

Nfkbie-deficiency leads to increased susceptibility to develop B-cell lymphoproliferative disorders in aged mice

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