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The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers

Nature Immunology volume 13, pages 1092–1100 (2012)Cite this article

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Abstract

Germinal centers (GCs) are sites of intense B cell proliferation and are central for T cell–dependent antibody responses. However, the role of c-Myc, a key cell-cycle regulator, in this process has been questioned. Here we identified c-Myc+ B cell subpopulations in immature and mature GCs and found, by genetic ablation of Myc, that they had indispensable roles in the formation and maintenance of GCs. The identification of these functionally critical cellular subsets has implications for human B cell lymphomagenesis, which originates mostly from GC B cells and frequently involves MYC chromosomal translocations. As these translocations are generally dependent on transcription of the recombining partner loci, the c-Myc+ GC subpopulations may be at a particularly high risk for malignant transformation.

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Figure 1: Enrichment for the expression of c-Myc target genes in GC B cells.
Figure 2: A fraction of both newly formed and mature GC B cells are c-Myc+.
Figure 3: Early GC B cells express both c-Myc and Bcl-6 and are hyperproliferative.
Figure 4: GC formation requires c-Myc.
Figure 5: Enforced Bcl6 expression does not restore GC formation after ablation of Myc.
Figure 6: The c-Myc+ GC B cells in mature GCs localize to the LZ and have an activated phenotype.
Figure 7: A large fraction of c-Myc+ mature GC B cells are in cell cycle, and these cells are essential for GC maintenance.

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Acknowledgements

We thank D. Ghitza, J. Wang, J. Grundy, J. Xia, C. Grosse, B. Wollert-Wulff and M. Bamberg for technical assistance; M. Ottaviano and M. Bezohra for administrative assistance; the Rajewsky laboratory members for critical comments and suggestions; and D. Dominguez-Sola and R. Dalla-Favera for sharing unpublished results. Supported by the National Cancer Institute (PO1CA092625 to K.R.), the Leukemia and Lymphoma Society (K.R. and D.P.C.) and the European Research Council (K.R.).

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Authors and Affiliations

  1. Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, Massachusetts, USA

    Dinis Pedro Calado, Alex Pellerin & Klaus Rajewsky

  2. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Dinis Pedro Calado, Karl Köchert, Martin Janz & Klaus Rajewsky

  3. Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Yoshiteru Sasaki

  4. Department of Pediatric Oncology, Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

    Susana A Godinho

  5. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA

    Barry P Sleckman

  6. Department of Immunology and Oncology, National Centre for Biotechnology, Madrid, Spain

    Ignacio Moreno de Alborán

  7. Hematology, Oncology and Tumor Immunology, Charité, University Medical School, Berlin, Germany

    Martin Janz

  8. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Scott Rodig

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Contributions

D.P.C. and K.R. conceived of the work and designed experiments; D.P.C., Y.S., S.A.G., A.P., K.K., M.J. and S.R. did experiments and/or analyzed data; B.P.S. and I.M.d.A. contributed reagents; D.P.C. and K.R. supervised all aspects of the project; D.P.C. and K.R. wrote the manuscript; and all authors discussed results and edited the manuscript.

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Correspondence to Dinis Pedro Calado or Klaus Rajewsky.

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Calado, D., Sasaki, Y., Godinho, S. et al. The cell-cycle regulator c-Myc is essential for the formation and maintenance of germinal centers. Nat Immunol 13, 1092–1100 (2012). https://doi.org/10.1038/ni.2418

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