title: The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry.
abstract: 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.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dominguez-Sola
authors.forename: Gabriel D
authors.initials: GD
authors.lastname: Victora
authors.forename: Carol Y
authors.initials: CY
authors.lastname: Ying
authors.forename: Ryan T
authors.initials: RT
authors.lastname: Phan
authors.forename: Masumichi
authors.initials: M
authors.lastname: Saito
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D016259:Genes, myc / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D049452:Green Fluorescent Proteins; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000235:genetics* / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D015703:Antigens, CD; D051560:Proto-Oncogene Proteins c-bcl-6; D011947:Receptors, Antigen, B-Cell; D049452:Green Fluorescent Proteins