The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry

• Published in: Nature immunology Vol. 13; no. 11; pp. 1083 - 1091
• Main Authors: Dominguez-Sola, David, Victora, Gabriel D, Ying, Carol Y, Phan, Ryan T, Saito, Masumichi, Nussenzweig, Michel C, Dalla-Favera, Riccardo
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2012; Nature Publishing Group
• Subjects: 631/250/2152/2153/1982; 631/250/580; 631/67/395; 692/699/67/1990/291; Analysis; Animals; Antigens, CD - genetics; Antigens, CD - immunology; B cells; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Biomedicine; Cell Cycle - genetics; Cell Cycle - immunology; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - immunology; Gene Expression Regulation; Genes, myc - immunology; Genes, Reporter; Germinal Center - immunology; Germinal Center - metabolism; Germinal Center - pathology; Green Fluorescent Proteins; Immunology; Infectious Diseases; Lymphoma - genetics; Lymphoma - metabolism; Lymphoma - pathology; Mice; Mice, Transgenic; Physiological aspects; Proto-Oncogene Proteins c-bcl-6 - genetics; Proto-Oncogene Proteins c-bcl-6 - immunology; Proto-oncogenes; Receptors, Antigen, B-Cell - genetics; Receptors, Antigen, B-Cell - immunology; Signal Transduction; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology
• ISSN: 1529-2908; 1529-2916; 1529-2916
• DOI: 10.1038/ni.2428

The molecular control of germinal center selection is still being determined. Dalla-Favera and colleagues show that the cell-cycle regulator c-Myc is essential for B cell selection and reentry into the germinal center. After antigenic challenge, B cells enter the dark zone (DZ) of germinal centers (GCs) to proliferate and hypermutate their immunoglobulin genes. Mutants with greater affinity for the antigen are positively selected in the light zone (LZ) to either differentiate into plasma and memory cells or reenter the DZ. The molecular circuits that govern positive selection in the GC are not known. We show here that the GC reaction required biphasic regulation of expression of the cell-cycle regulator c-Myc that involved its transient induction during early GC commitment, its repression by Bcl-6 in DZ B cells and its reinduction in B cells selected for reentry into the DZ. Inhibition of c-Myc in vivo led to GC collapse, which indicated an essential role for c-Myc in GCs. Our results have implications for the mechanism of GC selection and the role of c-Myc in lymphomagenesis.