Key Points• FOXP1 directly represses multiple proapoptotic genes in primary mature human B cells and DLBCL cell lines.• FOXP1 cooperates with NF-kB signaling to promote expansion of primary mature human B cells by inhibition of caspase-dependent apoptosis.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 kB (NF-kB) 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-kB 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-kB activity to promote B-cell survival and can thereby contribute to B-cell homeostasis and lymphomagenesis. (Blood. 2014;124(23):3431-3440) IntroductionThe forkhead transcription factor FOXP1 plays an important role in a wide diversity of biological processes, including T-cell development and differentiation 1,2 and B-cell development and function. [3][4][5] Furthermore, FOXP1 has long been recognized as a potential oncogene in various types of B-cell non-Hodgkin lymphomas; however, its mode of oncogenic action is largely unknown. 6,7 In diffuse large B-cell lymphoma (DLBCL) and mucosaassociated lymphoid tissue (MALT) lymphoma, aberrantly high expression of FOXP1 is associated with poor prognosis and FOXP1-positive MALT lymphomas were shown to be at risk of transforming into aggressive DLBCLs. 8,9 This overexpression of FOXP1 can be caused by a t(3;14)(p14;q32) translocation, involving FOXP1 and IgH loci, which has recurrently been observed in MALT lymphoma and activated B-cell-like (ABC) DLBCL.10-13 FOXP1 expression is also frequently upregulated in ABC-DLBCL as a result of trisomy 3 or more restricted focal amplifications, 14 whereas aberrant Myc expression in transformed gastric MALT lymphomas leads to upregulation of FOXP1 due to repression of the FOXP1 targeting miRNA 34a. 15 Furthermore, expression levels of FOXP1 can be used as a discriminator between the ABC and germinal center (GC) subtypes of DLBCL, ...
The forkhead transcription factor FOXP1 is generally regarded as an oncogene in activated B cell-like diffuse large B-cell lymphoma. Previous studies have suggested that a small isoform of FOXP1 rather than full-length FOXP1, may possess this oncogenic activity. Corroborating those studies, we herein show that activated B cell-like diffuse large B-cell lymphoma cell lines and primary activated B cell-like diffuse large B-cell lymphoma cells predominantly express a small FOXP1 isoform, and that the 5′-end of the Foxp1 gene is a common insertion site in murine lymphomas in leukemia virus- and transposon-mediated insertional mutagenesis screens. By combined mass spectrometry, (quantative) reverse transcription polymerase chain reaction/sequencing, and small interfering ribonucleic acid-mediated gene silencing, we determined that the small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma lacks the N-terminal 100 amino acids of full-length FOXP1. Aberrant overexpression of this FOXP1 isoform (ΔN100) in primary human B cells revealed its oncogenic capacity; it repressed apoptosis and plasma cell differentiation. However, no difference in potency was found between this small FOXP1 isoform and full-length FOXP1. Furthermore, overexpression of full-length FOXP1 or this small FOXP1 isoform in primary B cells and diffuse large B-cell lymphoma cell lines resulted in similar gene regulation. Taken together, our data indicate that this small FOXP1 isoform and full-length FOXP1 have comparable oncogenic and transcriptional activity in human B cells, suggesting that aberrant expression or overexpression of FOXP1, irrespective of the specific isoform, contributes to lymphomagenesis. These novel insights further enhance the value of FOXP1 for the diagnostics, prognostics, and treatment of diffuse large B-cell lymphoma patients.
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