title: FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells.
abstract: The forkhead transcription factor FOXP1 is involved in B-cell development and function and is generally regarded as an oncogene in activated B-cell-like subtype of diffuse large B-cell lymphoma (DLBCL) and mucosa-associated lymphoid tissue lymphoma, lymphomas relying on constitutive nuclear factor κB (NF-κB) activity for survival. However, the mechanism underlying its putative oncogenic activity has not been established. By gene expression microarray, upon overexpression or silencing of FOXP1 in primary human B cells and DLBCL cell lines, combined with chromatin immunoprecipitation followed by next-generation sequencing, we established that FOXP1 directly represses a set of 7 proapoptotic genes. Low expression of these genes, encoding the BH3-only proteins BIK and Harakiri, the p53-regulatory proteins TP63, RASSF6, and TP53INP1, and AIM2 and EAF2, is associated with poor survival in DLBCL patients. In line with these findings, we demonstrated that FOXP1 promotes the expansion of primary mature human B cells by inhibiting caspase-dependent apoptosis, without affecting B-cell proliferation. Furthermore, FOXP1 is dependent upon, and cooperates with, NF-κB signaling to promote B-cell expansion and survival. Taken together, our data indicate that, through direct repression of proapoptotic genes, (aberrant) expression of FOXP1 complements (constitutive) NF-κB activity to promote B-cell survival and can thereby contribute to B-cell homeostasis and lymphomagenesis.
authors.affiliation: Department of Pathology and Lymphoma and Myeloma Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Martine
authors.initials: M
authors.lastname: van Keimpema
authors.affiliation: Department of Pathology and Lymphoma and Myeloma Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Leonie J
authors.initials: LJ
authors.lastname: Grüneberg
authors.affiliation: Division of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, The Netherlands;
authors.forename: Ruben
authors.initials: R
authors.lastname: van Boxtel
authors.affiliation: Department of Oncogenomics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; and.
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.affiliation: Department of Cell Biology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coffer
authors.affiliation: Department of Pathology and Lymphoma and Myeloma Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Steven T
authors.initials: ST
authors.lastname: Pals
authors.affiliation: Department of Pathology and Lymphoma and Myeloma Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;
authors.forename: Marcel
authors.initials: M
authors.lastname: Spaargaren
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology*; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000502:physiology*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology; D046228:Microarray Analysis; D016328:NF-kappa B / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; D012097:Repressor Proteins