TitleDownregulation of FOXP1 is required during germinal center B-cell function.
Publication TypeJournal Article
Year of Publication2013
AuthorsSagardoy, Ainara, Martinez-Ferrandis Jose I., Roa Sergio, Bunting Karen L., Aznar María Angela, Elemento Olivier, Shaknovich Rita, Fontan Lorena, Fresquet Vicente, Perez-Roger Ignacio, Robles Eloy F., De Smedt Linde, Sagaert Xavier, Melnick Ari, and Martinez-Climent Jose A.
JournalBlood
Volume121
Issue21
Pagination4311-20
Date Published2013 May 23
ISSN1528-0020
KeywordsAnimals, B-Lymphocytes, Cell Differentiation, Cell Line, DNA-Binding Proteins, Down-Regulation, Forkhead Transcription Factors, Germinal Center, Humans, Lymphoma, Mice, Mice, Transgenic, Palatine Tonsil, Proto-Oncogene Proteins c-bcl-6, Repressor Proteins, Transcriptional Activation
Abstract

<p>B-cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other transcriptional regulators. FOXP1 is a transcription factor that regulates early B-cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B-cell subpopulations revealed that FOXP1 shows the opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. Chromatin immunoprecipitation-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcriptional activator and repressor of genes involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in lymphoid cells. These mice exhibited irregular formation of splenic GCs, showing a modest increase in naïve and marginal-zone B cells and a significant decrease in GC B cells. Furthermore, aberrant expression of FOXP1 impaired transcription of noncoding γ1 germline transcripts and inhibited efficient class switching to the immunoglobulin G1 isotype. These studies show that FOXP1 is physiologically downregulated in GC B cells and that aberrant expression of FOXP1 impairs mechanisms triggered by B-cell activation, potentially contributing to B-cell lymphomagenesis.</p>

DOI10.1182/blood-2012-10-462846
Alternate JournalBlood
PubMed ID23580662
PubMed Central IDPMC3713421
Grant ListR01 CA104348 / CA / NCI NIH HHS / United States
R01-CA104348 / CA / NCI NIH HHS / United States