The forkhead transcription factor FOXP1 represses human plasma cell differentiation.
Expression of the forkhead transcription factor FOXP1 is essential for early B-cell development, whereas downregulation of FOXP1 at the germinal center (GC) stage is required for GC B-cell function. Aberrantly high FOXP1 expression is frequently observed in diffuse large B-cell lymphoma and mucosa-associated lymphoid tissue lymphoma, being associated with poor prognosis. Here, by gene expression analysis upon ectopic overexpression of FOXP1 in primary human memory B cells (MBCs) and B-cell lines, combined with chromatin immunoprecipitation and sequencing, we established that FOXP1 directly represses expression of PRDM1, IRF4, and XBP1, transcriptional master regulators of plasma cell (PC) differentiation. In accordance, FOXP1 is prominently expressed in primary human naive and MBCs, but expression strongly decreases during PC differentiation. Moreover, as compared with immunoglobulin (Ig) M(+) MBCs, IgG(+) MBCs combine lower expression of FOXP1 with an enhanced intrinsic PC differentiation propensity, and constitutive (over)expression of FOXP1 in B-cell lines and primary human MBCs represses their ability to differentiate into PCs. Taken together, our data indicate that proper control of FOXP1 expression plays a critical role in PC differentiation, whereas aberrant expression of FOXP1 might contribute to lymphomagenesis by blocking this terminal B-cell differentiation.
Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Amsterdam, The Netherlands;
Martine
M
van Keimpema
Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Amsterdam, The Netherlands;
Leonie J
LJ
Grüneberg
Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands;
Michal
M
Mokry
Hubrecht Institute for Developmental Biology and Stem Cell Research, and University Medical Center Utrecht, Utrecht, The Netherlands;
Ruben
R
van Boxtel
Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands; and.
Menno C
MC
van Zelm
Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
Paul
P
Coffer
Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Amsterdam, The Netherlands;
Steven T
ST
Pals
Department of Pathology, Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Academic Medical Center, Amsterdam, The Netherlands;
Marcel
M
Spaargaren
D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D010950:Plasma Cells / Q000166:cytology* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D012097:Repressor Proteins