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Immunity. 2015 Dec 15;43(6):1064-74. doi: 10.1016/j.immuni.2015.10.015. Epub 2015 Nov 24.

The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program.

Author information

1
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.
2
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
3
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
4
Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
5
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.

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.

PMID:
26620759
DOI:
10.1016/j.immuni.2015.10.015
[Indexed for MEDLINE]
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