The impact of transgenic Uchl1 on gene expression in germinal center B-cells from ImHABCL6 mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE76706 | GEO | 2016/01/12
SECONDARY ACCESSION(S): PRJNA308434
REPOSITORIES: GEO
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Project description:This study seeks to understand the mechanisms behind enhanced lymphomagenesis observed in ImHABCL6/Uchl1 mice compared with ImHABCL6 alone. As the lymphomas arise from germinal center (GC) B-cells, we reasoned that transgenic Uchl1 altered the gene expression patterns in GC B-cells from these animals. We therefore isolated pre-malignant GC B-cells and examined the gene expression patterns to identify pathways affected by the addition of Uchl1. Germinal center B-cells were isolated from from the spleens of ImHABCL6 and ImHABCL6/Uchl1 mutant mice (n= 3 each) after immunization with sheep red blood cells. RNA was extracted and hybridized to affymetrix mouse 430 2.0 arrays.
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Project description:The MEF2B transcription factor is frequently mutated in germinal center (GC)-derived B-cell lymphomas. Its N-terminal mutations drive lymphomagenesis by escaping interaction with transcriptional repressors, while the function of C-terminal mutations remains to be elucidated. Here, we show that MEF2B C-tail is physiologically phosphorylated at specific residues and phosphorylation at S324 is impaired by lymphoma-associated mutations. Lack of phosphorylation at S324 enhances the interaction of MEF2B with the SWI/SNF chromatin remodeling complex, leading to higher transcriptional activity. In addition, these mutants show an increased protein stability due to impaired interaction with the CUL3/KLHL12 ubiquitin complex. Mice expressing a phosphorylation-deficient lymphoma-associated MEF2B mutant display GC enlargement and develop GC-derived lymphomas, when crossed with Bcl2 transgenic mice. These results unveil converging mechanisms of action for a diverse spectrum of MEF2B mutations, all leading to its dysregulation and GC B-cell lymphomagenesis. These assorted mechanisms provide additional opportunities for the development of targeted therapeutic approaches.
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Project description:The MEF2B transcription factor is frequently mutated in germinal center (GC)-derived B-cell lymphomas. Its N-terminal mutations drive lymphomagenesis by escaping interaction with transcriptional repressors, while the function of C-terminal mutations remains to be elucidated. Here, we show that MEF2B C-tail is physiologically phosphorylated at specific residues and phosphorylation at S324 is impaired by lymphoma-associated mutations. Lack of phosphorylation at S324 enhances the interaction of MEF2B with the SWI/SNF chromatin remodeling complex, leading to higher transcriptional activity. In addition, these mutants show an increased protein stability due to impaired interaction with the CUL3/KLHL12 ubiquitin complex. Mice expressing a phosphorylation-deficient lymphoma-associated MEF2B mutant display GC enlargement and develop GC-derived lymphomas, when crossed with Bcl2 transgenic mice. These results unveil converging mechanisms of action for a diverse spectrum of MEF2B mutations, all leading to its dysregulation and GC B-cell lymphomagenesis. These assorted mechanisms provide additional opportunities for the development of targeted therapeutic approaches.
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Project description:Protection against deadly pathogens requires the production of high-affinity antibodies by B cells. High-affinity antibody-forming cells are generated in germinal centers (GC) as a result of a developmental program that is commonly altered in 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 often constitutively activated in GC-derived Non-Hodgkin lymphomas (NHL), but its function in these cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells causes a profound impairment in GC responses, memory B cell formation and humoral immunity. Mechanistically, Ezh2 protected GC B cells against AID mutagenesis, facilitated cell-cycle progression independent of p16INK4a repression and silenced plasma cell determinants Blimp1 and Irf4. Likewise, EZH2 inhibition in GC-derived NHL cells induced tumor suppressor BLIMP1, which impaired tumor growth. In conclusion, in GC B cells Ezh2 sustains AID function and prevents terminal differentiation to allow antibody diversification and affinity maturation. Dysregulation of such mechanisms may facilitate lymphomagenesis and identifies EZH2 as possible therapeutic target in NHL and other GC-derived B cell diseases. In this study, two independent primary samples of splenic GC B cells from C5/BL/6J mice were subjected to H3K27me3 and H3K4me3 ChIP-sequencing. A totale of 6 samples, including input samples, were subjected to ultra-deep sequencing.
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Project description:The EZH2 histone methyltransferase is highly expressed in germinal center (GC) B-cells and targeted by somatic mutations in B-cell lymphomas. Here we find that EZH2 deletion or pharmacologic inhibition suppresses GC formation and functions in mice. EZH2 represses proliferation checkpoint genes and helps establish bivalent chromatin domains at key regulatory loci to transiently suppress GC B-cell differentiation. Somatic mutations reinforce these physiological effects through enhanced silencing of EZH2 targets in B-cells, and in human B-cell lymphomas. Conditional expression of mutant EZH2 in mice induces GC hyperplasia and accelerated lymphomagenesis in cooperation with BCL2. GCB-type DLBCLs are mostly addicted to EZH2, regardless of mutation status, but not the more differentiated ABC-type DLBCLs, thus clarifying the therapeutic scope of EZH2 targeting.
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Project description:Protection against deadly pathogens requires the production of high-affinity antibodies by B cells. High-affinity antibody-forming cells are generated in germinal centers (GC) as a result of a developmental program that is commonly altered in 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 often constitutively activated in GC-derived Non-Hodgkin lymphomas (NHL), but its function in these cells remains largely unknown. Herein, we show that Ezh2 inactivation in mouse GC B cells causes a profound impairment in GC responses, memory B cell formation and humoral immunity. Mechanistically, Ezh2 protected GC B cells against AID mutagenesis, facilitated cell-cycle progression independent of p16INK4a repression and silenced plasma cell determinants Blimp1 and Irf4. Likewise, EZH2 inhibition in GC-derived NHL cells induced tumor suppressor BLIMP1, which impaired tumor growth. In conclusion, in GC B cells Ezh2 sustains AID function and prevents terminal differentiation to allow antibody diversification and affinity maturation. Dysregulation of such mechanisms may facilitate lymphomagenesis and identifies EZH2 as possible therapeutic target in NHL and other GC-derived B cell diseases.
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