MEF2B C-terminal mutations enhance transcriptional activity and stability to drive B cell lymphomagenesis

Chuanjiang Yu, Qiong Shen, Antony B. Holmes, Tongwei Mo, Anna Tosato, Rajesh Kumar Soni, Clarissa Corinaldesi, Sanjay Koul, Laura Pasqualucci, Shafinaz Hussein, Farhad Forouhar, Riccardo Dalla-Favera () and Katia Basso ()
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Chuanjiang Yu: Columbia University
Qiong Shen: Columbia University
Antony B. Holmes: Columbia University
Tongwei Mo: Columbia University
Anna Tosato: Columbia University
Rajesh Kumar Soni: Columbia University
Clarissa Corinaldesi: Columbia University
Sanjay Koul: Bayside
Laura Pasqualucci: Columbia University
Shafinaz Hussein: Icahn School of Medicine at Mount Sinai
Farhad Forouhar: Columbia University
Riccardo Dalla-Favera: Columbia University
Katia Basso: Columbia University

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract The myocyte enhancer factor 2B (MEF2B) transcription factor is frequently mutated in germinal center (GC)-derived B-cell lymphomas. Its ammino (N)-terminal mutations drive lymphomagenesis by escaping interaction with transcriptional repressors, while the function of carboxy (C)-terminal mutations remains to be elucidated. Here, we show that MEF2B C-tail is physiologically phosphorylated at specific residues and phosphorylation at serine (S)324 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.

Date: 2024
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DOI: 10.1038/s41467-024-51644-8

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