Germinal Center B cell transcriptional profiles in Mef2b mouse models
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA434245 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6730070.fastq.gz | Fastqsanger.gz | |||
| SRR6730080.fastq.gz | Fastqsanger.gz | |||
| SRR6730090.fastq.gz | Fastqsanger.gz | |||
| SRR6730071.fastq.gz | Fastqsanger.gz | |||
| SRR6730081.fastq.gz | Fastqsanger.gz |
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Project description:The MEF2B transcription factor is recurrently mutated in germinal-center (GC)-derived B-cell lymphomas, but its role in normal and neoplastic GC development is unknown. Here we identify MEF2B transcriptional targets in GC, which indicate its control of cell proliferation, apoptosis, GC confinement and differentiation. Consistently, Mef2b deletion reduces GC formation in mice. The most common tumor-associated MEF2B mutant (MEF2BD83V) is hypomorphic, but escapes binding and negative regulation by Cabin1 and HDACs. Mef2bD83V expression leads to GC enlargement and GC-derived tumors in 25% of the animals. This phenotype becomes fully penetrant in combination with BCL2 de-regulation, an event commonly associated with MEF2B mutations in human lymphoma. These results identify MEF2B as a critical GC regulator, and as a dominant oncogene in lymphomagenesis.
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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:Chromatin binding of MEF2B and SMARCA4 in normal human germinal center B cells
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Project description:The MEF2B transcription factor is recurrently mutated in germinal-center (GC)-derived B-cell lymphomas, but its role in normal and neoplastic GC development is unknown. Here we identify MEF2B transcriptional targets in GC, which indicate its control of cell proliferation, apoptosis, GC confinement and differentiation. Consistently, Mef2b deletion reduces GC formation in mice. The most common tumor-associated MEF2B mutant (MEF2BD83V) is hypomorphic, but escapes binding and negative regulation by Cabin1 and HDACs. Mef2bD83V expression leads to GC enlargement and GC-derived tumors in 25% of the animals. This phenotype becomes fully penetrant in combination with BCL2 de-regulation, an event commonly associated with MEF2B mutations in human lymphoma. These results identify MEF2B as a critical GC regulator, and as a dominant oncogene in lymphomagenesis.
2018-09-10 | GSE110682 | GEO