title: The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program.
abstract: The pathways regulating formation of the germinal center (GC) dark zone (DZ) and light zone (LZ) are unknown. In this study we show that FOXO1 transcription factor expression was restricted to the GC DZ and was required for DZ formation, since its absence in mice led to the loss of DZ gene programs and the formation of LZ-only GCs. FOXO1-negative GC B cells displayed normal somatic hypermutation but defective affinity maturation and class switch recombination. The function of FOXO1 in sustaining the DZ program involved the trans-activation of the chemokine receptor CXCR4, and cooperation with the BCL6 transcription factor in the trans-repression of genes involved in immune activation, DNA repair, and plasma cell differentiation. These results also have implications for the role of FOXO1 in lymphomagenesis because they suggest that constitutive FOXO1 activity might be required for the oncogenic activity of deregulated BCL6 expression.
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address: david.dominguez-sola@mssm.edu.
authors.forename: David
authors.initials: D
authors.lastname: Dominguez-Sola
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kung
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Antony B
authors.initials: AB
authors.lastname: Holmes
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Wells
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors.forename: Tongwei
authors.initials: T
authors.lastname: Mo
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Katia
authors.initials: K
authors.lastname: Basso
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Genetics and Development, Columbia University, New York, NY 10032, USA; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA. Electronic address: rd10@cumc.columbia.edu.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Dalla-Favera
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse