The FOXO1 Transcription Factor Instructs the Germinal Center Dark Zone Program

被引：192
作者：
Dominguez-Sola, David [1 ,6 ,7 ,8 ]
Kung, Jennifer
Holmes, Antony B. [1 ]
Wells, Victoria A. [1 ]
Mo, Tongwei [1 ]
Basso, Katia [1 ,2 ]
Dalla-Favera, Riccardo [1 ,2 ,3 ,4 ,5 ]
机构：
[1] Columbia Univ, Inst Canc Genet, New York, NY 10032 USA
[2] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA
[3] Columbia Univ, Dept Genet & Dev, New York, NY 10032 USA
[4] Columbia Univ, Dept Microbiol & Immunol, New York, NY 10032 USA
[5] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA
[6] Icahn Sch Med Mt Sinai, Dept Oncol Sci, New York, NY 10029 USA
[7] Icahn Sch Med Mt Sinai, Dept Pathol, New York, NY 10029 USA
[8] Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA
来源：
IMMUNITY | 2015年 / 43卷 / 06期
关键词：
PLASMA-CELL DIFFERENTIATION; CLASS-SWITCH RECOMBINATION; B-CELLS; AFFINITY MATURATION; BCL6; EXPRESSION; DYNAMICS; GENES; IDENTIFICATION; CONTRIBUTES;
D O I：
10.1016/j.immuni.2015.10.015
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
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.
引用
收藏
页码：1064 / 1074
页数：11
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