MEF2B Mutations Are Functionally Significant in DLBCL

Expression of B-cell lymphoma 6 (BCL6), an oncogene that encodes a transcriptional repressor and critical regulator of the germinal center (GC) B-cell lineage, is frequently deregulated in the GC B-cell–derived non-Hodgkin lymphomas diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The gene encoding the transcriptional coactivator myocyte enhancer factor 2B (MEF2B) is also recurrently mutated in these tumors, but the functional significance of these mutations is unknown. Ying and colleagues identified 11 somatic, heterozygous MEF2B mutations in a large panel of DLBCL and follicular lymphoma samples and cell lines; the majority of these were missense mutations within the N-terminus of MEF2B, which controls its transcriptional activity, but frameshift and nonsense mutations in the C-terminal region of MEF2B were also detected and predicted to yield truncated proteins or isoform switching. MEF2B was expressed in activated GC B cells and directly activated BCL6 transcription in both normal GC B cells and DLBCL cell lines, suggesting that MEF2B functions upstream of BCL6 to define GC B cells and that MEF2B mutations may contribute to lymphomagenesis. Consistent with this idea, depletion of MEF2B impaired the proliferation of DLBCL cells, in part due to diminished BCL6 expression. N-terminal mutations prevented the interaction of MEF2B with its corepressor, calcineurin binding protein 1 (CABIN1), and reduced recruitment of CABIN1 to the BCL6 promoter, resulting in augmented MEF2B transcriptional activity and increased BCL6-dependent gene repression in DLBCL cells. In contrast, C-terminal substitutions prevented protein kinase A-dependent phosphorylation and monosumoylation of MEF2B, thereby disrupting the inhibitory effects of these modifications on MEF2B transcriptional activity. These findings establish MEF2B mutation as an alternative mechanism to activate BCL6 in DLBCL and suggest that inhibition of MEF2B may suppress induction of BCL6 and other GC B-cell–specific genes important for lymphomagenesis.

Ying CY, Dominguez-Sola D, Fabi M, Lorenz IC, Hussein S, Bansal M, et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat Immunol 2013;14:1084–92.

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