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

Nature Immunology volume 14, pages 1084–1092 (2013)Cite this article

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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.

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Figure 1: MEF2B is targeted predominantly by missense mutations in DLBCL and FL.
Figure 2: MEF2B is expressed in GC B cells.
Figure 3: BCL6 is a direct transcriptional target of MEF2B in GC B cells.
Figure 4: MEF2B is required for cell-cycle progression and proliferation in DLBCL.
Figure 5: N-terminal substitutions of MEF2B enhance BCL6 transcription and correlate with increased biological activity of Bcl-6 in cases of primary DLBCL.
Figure 6: MEF2B proteins with N-terminal substitutions fail to bind CABIN1 and escape its corepressor activity.
Figure 7: MEF2B proteins with truncation at the C terminus escape negative regulation by PKA-dependent phosphorylation.
Figure 8: C-terminal substitutions of MEF2B abrogate negative regulation of MEF2B by phosphorylation-dependent sumoylation.

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Acknowledgements

We thank A. Grunn, M. Fangazio and M. Vasishtha for help with the sequencing analysis; C. Scuoppo for advice on and reagents for the inducible lentiviral vector system; A. Holmes for statistical analysis (analysis of variance); A. Zelent (The Institute of Cancer Research, London) for antibody to HDAC9; E. Yeh (MD Anderson) for depositing the plasmid encoding Ubc9 at Addgene; R.T. Hay (University of Dundee) for the expression plasmid encoding hemagglutinin-tagged SUMO1; and the Flow Cytometry facility of the Herbert Irving Comprehensive Cancer Center. Supported by the US National Institutes of Health (PO1-CA092625 and RO1-CA37295 to R.D.-F.), the Leukemia and Lymphoma Society (to R.D.-F.), the National Cancer Institute of the US National Institutes of Health (5K99 CA151827 to D.D.-S.) and the Stewart Trust (K.B.). L.P. is on leave from the University of Perugia Medical School, Perugia, Italy.

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  1. Ivo C Lorenz

    Present address: Present address: Boehringer Ingelheim, Ridgefield, Connecticut, USA.,

Authors and Affiliations

  1. Institute for Cancer Genetics, Columbia University, New York, New York, USA

    Carol Y Ying, David Dominguez-Sola, Melissa Fabi, Ivo C Lorenz, Shafinaz Hussein, Andrea Califano, Laura Pasqualucci, Katia Basso & Riccardo Dalla-Favera

  2. Department of Pathology and Cell Biology, Columbia University, New York, New York, USA

    Shafinaz Hussein, Laura Pasqualucci, Katia Basso & Riccardo Dalla-Favera

  3. Joint Centers for Systems Biology, Columbia University, New York, New York, USA

    Mukesh Bansal & Andrea Califano

  4. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York, USA

    Andrea Califano, Laura Pasqualucci & Riccardo Dalla-Favera

  5. Department of Genetics and Development, Columbia University, New York, New York, USA

    Riccardo Dalla-Favera

  6. Department of Microbiology and Immunology, Columbia University, New York, New York, USA

    Riccardo Dalla-Favera

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Contributions

C.Y.Y. and R.D.-F. designed the study and wrote the manuscript; C.Y.Y. did experiments and analyzed data; D.D.-S. did and contributed to the design and execution of the experiments and data analysis; M.F. did coimmunoprecipitation assays; I.C.L. did structural analysis; S.H. contributed to the immunofluorescence staining; M.B. did bioinformatics analysis, supervised by A.C.; L.P. did and supervised genomic analysis; K.B. contributed to the original design of the study; D.D.-S., K.B., L.P. and I.C.L. edited the manuscript; and all authors read and approved of the manuscript.

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Correspondence to Riccardo Dalla-Favera.

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Ying, C., Dominguez-Sola, D., Fabi, M. et al. MEF2B mutations lead to deregulated expression of the oncogene BCL6 in diffuse large B cell lymphoma. Nat Immunol 14, 1084–1092 (2013). https://doi.org/10.1038/ni.2688

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