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Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis
- Source :
- Europe PubMed Central
- Publication Year :
- 2014
- Publisher :
- American Society for Clinical Investigation, 2014.
-
Abstract
- Protection against deadly pathogens requires the production of high-affinity antibodies by B cells, which are generated in germinal centers (GCs). Alteration of the GC developmental program is common in many B cell malignancies. Identification of regulators of the GC response is crucial to develop targeted therapies for GC B cell dysfunctions, including lymphomas. The histone H3 lysine 27 methyltransferase enhancer of zeste homolog 2 (EZH2) is highly expressed in GC B cells and is often constitutively activated in GC-derived non-Hodgkin lymphomas (NHLs). The function of EZH2 in GC B cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells caused profound impairment of GC responses, memory B cell formation, and humoral immunity. EZH2 protected GC B cells against activation-induced cytidine deaminase (AID) mutagenesis, facilitated cell cycle progression, and silenced plasma cell determinant and tumor suppressor B-lymphocyte–induced maturation protein 1 (BLIMP1). EZH2 inhibition in NHL cells induced BLIMP1, which impaired tumor growth. In conclusion, EZH2 sustains AID function and prevents terminal differentiation of GC B cells, which allows antibody diversification and affinity maturation. Dysregulation of the GC reaction by constitutively active EZH2 facilitates lymphomagenesis and identifies EZH2 as a possible therapeutic target in NHL and other GC-derived B cell diseases. Published version
- Subjects :
- Lymphoma
Gene Rearrangement, B-Lymphocyte, Heavy Chain
Apoptosis
Plasma cell
Transgenic
Mice
Clinical investigation
Memory B cell
Gene Rearrangement
B-Lymphocytes
Medicine (all)
Lymphoma, Non-Hodgkin
Lymphopoiesis
Cell Cycle
EZH2
B-Lymphocyte
Polycomb Repressive Complex 2
Humoral
General Medicine
Cell cycle
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
Histone methyltransferase
Corrigendum
Research Article
Non-Hodgkin
Science::Biological sciences::Molecular biology [DRNTU]
Mice, Transgenic
macromolecular substances
Biology
Animals
Cytidine Deaminase
DNA Damage
Enzyme Activation
Gene Expression Regulation
Neoplastic
Heavy Chain
Gene Silencing
Germinal Center
Immunity
Immunologic Memory
Methylation
Protein Processing
Post-Translational
Transcription Factors
NO
Affinity maturation
medicine
Enhancer of Zeste Homolog 2 Protein
B cell
Germinal center
Immunity, Humoral
Immunology
Cancer research
Positive Regulatory Domain I-Binding Factor 1
Protein Processing, Post-Translational
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Europe PubMed Central
- Accession number :
- edsair.doi.dedup.....d26e355efb196fc989693fba81803c01