MEF2B Instructs Germinal Center Development and Acts as an Oncogene in B Cell Lymphomagenesis

The gene encoding theMEF2Btranscription factor ismutated in germinal center (GC)-derivedB cell lymphomas, but its role inGC development and lymphomagenesis is unknown.We demonstrate that Mef2b deletion reduces GC formation inmice and identify MEF2B transcriptional targets in GC, with roles in cell proliferation, apoptosis, GC confinement, and differentiation. The most common lymphoma-associated MEF2B mutant (MEF2BD83V) is hypomorphic, yet escapes binding and negative regulation by components of the HUCA complex and class IIa HDACs. Mef2bD83V expression in mice leads to GC enlargement and lymphoma development, a phenotype that becomes fully penetrant in combination with BCL2 de-regulation, an event associated with human MEF2B mutations. These results identify MEF2B as a critical GC regulator and a driver oncogene in lymphomagenesis.