MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma

Nat Immunol. 2013 Oct;14(10):1084-92. doi: 10.1038/ni.2688. Epub 2013 Aug 25.

Abstract

MEF2B encodes a transcriptional activator and is mutated in ∼11% of diffuse large B cell lymphomas (DLBCLs) and ∼12% of follicular lymphomas (FLs). Here we found that MEF2B directly activated the transcription of the proto-oncogene BCL6 in normal germinal-center (GC) B cells and was required for DLBCL proliferation. Mutation of MEF2B resulted in enhanced transcriptional activity of MEF2B either through disruption of its interaction with the corepressor CABIN1 or by rendering it insensitive to inhibitory signaling events mediated by phosphorylation and sumoylation. Consequently, the transcriptional activity of Bcl-6 was deregulated in DLBCLs with MEF2B mutations. Thus, somatic mutations of MEF2B may contribute to lymphomagenesis by deregulating BCL6 expression, and MEF2B may represent an alternative target for blocking Bcl-6 activity in DLBCLs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / chemistry
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • B-Lymphocytes / metabolism
  • B-Lymphocytes / pathology
  • Cell Cycle / genetics
  • Cell Proliferation
  • Cluster Analysis
  • Computational Biology
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Germinal Center / metabolism
  • Germinal Center / pathology
  • Humans
  • Lymphoma, Follicular / genetics
  • Lymphoma, Follicular / metabolism
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • MADS Domain Proteins / chemistry
  • MADS Domain Proteins / genetics*
  • MADS Domain Proteins / metabolism
  • MEF2 Transcription Factors
  • Mice
  • Molecular Docking Simulation
  • Mutation*
  • Myogenic Regulatory Factors / chemistry
  • Myogenic Regulatory Factors / genetics*
  • Myogenic Regulatory Factors / metabolism
  • Protein Binding
  • Protein Conformation
  • Proto-Oncogene Proteins c-bcl-6 / genetics*
  • Sumoylation / genetics
  • Transcription, Genetic

Substances

  • Adaptor Proteins, Signal Transducing
  • CABIN1 protein, human
  • MADS Domain Proteins
  • MEF2 Transcription Factors
  • MEF2B protein, human
  • Myogenic Regulatory Factors
  • Proto-Oncogene Proteins c-bcl-6
  • Cyclic AMP-Dependent Protein Kinases