FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells

Keimpema, Martine van; Grüneberg, Leonie J.; Mokrý, Michal; Boxtel, Ruben van; Koster, Jan; Coffer, Paul J.; Pals, Steven T.; Spaargaren, Marcel

doi:10.1182/blood-2014-01-553412

Cited by 87 publications

(80 citation statements)

References 74 publications

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“…MBCs were isolated as previously described. 25 IgA 2 population, using antibodies against CD19, CD27, and PEconjugated antibodies against IgM and IgA (Southern Biotech). Tonsils were obtained from children undergoing routine tonsillectomy as previously described.…”

Section: B-cell Isolationmentioning

confidence: 99%

“…Tonsils were obtained from children undergoing routine tonsillectomy as previously described. 25 Tonsillar B-cell subsets were isolated by FACSAria sorting using an PE-conjugated antibody against CD19 (DAKO), an FITC-conjugated antibody against IgD (Southern Biotech), and an APC-conjugated antibody against CD38 (BD).…”

Section: B-cell Isolationmentioning

confidence: 99%

“…[21][22][23][24] In accordance, we recently demonstrated that FOXP1 overexpression in primary human B cells cooperates with nuclear factor kB pathway activity to promote B-cell survival. 14,25 Furthermore, a recent study by Sagardoy et al 26 showed that FOXP1 expression is temporarily repressed at the GC stage, which is needed for appropriate GC B-cell function. 26 However, potential functions of FOXP1 in differentiation of post-GC B cells have not yet been assessed.…”

Section: Introductionmentioning

confidence: 99%

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The forkhead transcription factor FOXP1 represses human plasma cell differentiation

Keimpema

Grüneberg

Mokrý

et al. 2015

Blood

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Section: B-cell Isolationmentioning

confidence: 99%

Section: B-cell Isolationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The forkhead transcription factor FOXP1 represses human plasma cell differentiation

Keimpema

Grüneberg

Mokrý

et al. 2015

Blood

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“…18 Another study demonstrated that FOXP1 suppresses apoptosis of DLBCL cells by transcriptional repression of a set of proapoptotic target genes, which includes the BH3-only protein BIK and several p53 regulatory proteins. 19 Here, we have combined a genome-wide search for direct FOXP1 targets using chromatin immunoprecipitation (ChIP) followed by next-generation sequencing and RNA interference with functional screening for biologically relevant target genes to identify novel tumor suppressor proteins in FOXP1-positive DLBCL. We provide evidence that the repressed FOXP1 target sphingosine-1-phosphate receptor 2 (S1PR2) has robust tumor suppressive activity in DLBCL cells in vitro and in vivo and represents an excellent prognostic biomarker that, either alone or in combination with FOXP1 expression, accurately predicts survival of ABC DLBCL patients.…”

Section: Introductionmentioning

confidence: 99%

The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling

Flori

Schmid

Sumrall

et al. 2016

Blood

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Key Points• The sphingosine-1-phosphate receptor 2 (S1PR2) is a novel tumor suppressor and survival prognosticator in the ABC subtype of DLBCL.• S1PR2 is a direct, repressed FOXP1 target; ectopic S1PR2 expression induces apoptosis in DLBCL cells in vitro and prevents tumor growth.Aberrant expression of the oncogenic transcription factor forkhead box protein 1 (FOXP1) is a common feature of diffuse large B-cell lymphoma (DLBCL). We have combined chromatin immunoprecipitation and gene expression profiling after FOXP1 depletion with functional screening to identify targets of FOXP1 contributing to tumor cell survival. We find that the sphingosine-1-phosphate receptor 2 (S1PR2) is repressed by FOXP1 in activated B-cell (ABC) and germinal center B-cell (GCB) DLBCL cell lines with aberrantly high FOXP1 levels; S1PR2 expression is further inversely correlated with FOXP1 expression in 3 patient cohorts. Ectopic expression of wild-type S1PR2, but not a point mutant incapable of activating downstream signaling pathways, induces apoptosis in DLBCL cells and restricts tumor growth in subcutaneous and orthotopic models of the disease. The proapoptotic effects of S1PR2 are phenocopied by ectopic expression of the small G protein Ga13 but are independent of AKT signaling. We further show that low S1PR2 expression is a strong negative prognosticator of patient survival, alone and especially in combination with high FOXP1 expression. The S1PR2 locus has previously been demonstrated to be recurrently mutated in GCB DLBCL; the transcriptional silencing of S1PR2 by FOXP1 represents an alternative mechanism leading to inactivation of this important hematopoietic tumor suppressor. (Blood. 2016;127(11):1438-1448 IntroductionThe forkhead box protein 1 (FOXP1) transcription factor is aberrantly expressed in the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) and represents a widely accepted biomarker for survival prognostication in DLBCL. The FOXP1 genomic locus is recurrently targeted by genomic rearrangements in ABC DLBCL as well as in marginal zone lymphoma of mucosa-associated lymphoid tissue and in chronic lymphocytic leukemia, which correlates with a poor prognosis in each disease entity. 1-3 Primary FOXP1 translocations predominantly involve the immunoglobulin heavy chain locus, leading to overexpression of the full-length protein 3 ; in contrast, the rare nonimmunoglobulin rearrangements of FOXP1 generate N-truncated isoforms that are believed to drive disease progression rather than initiation. 4 Most FOXP1-expressing lymphomas exhibit no apparent structural aberrations of the gene 5 ; the short, putatively oncogenic isoforms in particular are highly expressed from the wild-type locus in ABC DLBCL as a consequence of "normal" B-cell activation. 6 We have shown earlier that aberrant FOXP1 expression in ABC DLBCL may alternatively also result from dysregulated posttranscriptional regulation. 7,8 FOXP1 protein levels are regulated by the microRNA miR-34a, which itself is either transcriptionally or ep...

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“…32 Direct FOXP1 target genes, including PAX5, PRDM1, and POU2F1, support a functional role in the GC reaction. 32 Recent studies have provided insight into FOXP1 function in DLBCL cells, indicating contributions to proliferation, 33 inhibition of apoptosis to compliment NF-kB-dependent regulation of proliferation, 34 and Wnt signaling. 25 However, further understanding of FOXP1 isoform expression and functionality is required to pursue emerging evidence indicating that FOXP1 L and FOXP1 S proteins have distinct functions.…”

mentioning

confidence: 99%

N-terminally truncated FOXP1 protein expression and alternate internal FOXP1 promoter usage in normal and malignant B cells

et al. 2016

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Strong FOXP1 protein expression is a poor risk factor in diffuse large B-cell lymphoma and has been linked to an activated B-cell-like subtype, which preferentially expresses short FOXP1 (FOXP1 S ) proteins. However, both short isoform generation and function are incompletely understood. Here we prove by mass spectrometry and Nterminal antibody staining that FOXP1 S proteins in activated B-cell-like diffuse large B-cell lymphoma are N-terminally truncated. Furthermore, a rare strongly FOXP1-expressing population of normal germinal center B cells lacking the N-terminus of the regular long protein (FOXP1 L ) was identified. Exon-targeted silencing and transcript analyses identified three alternate 5ʹ non-coding exons [FOXP1-Ex6b(s), FOXP1-Ex7b and FOXP1-Ex7c], downstream of at least two predicted promoters, giving rise to FOXP1 S proteins. These were differentially controlled by B-cell activation and methylation, conserved in murine lymphoma cells, and significantly correlated with FOXP1 S protein expression in primary diffuse large B-cell lymphoma samples. Alternatively spliced isoforms lacking exon 9 (e.g. isoform 3) did not encode FOXP1 S , and an alternate long human FOXP1 protein (FOXP1 AL ) likely generated from a FOXP1-Ex6b(L) transcript was detected. The ratio of FOXP1 L :FOXP1 S isoforms correlated with differential expression of plasmacytic differentiation markers in U-2932 subpopulations, and altering this ratio was sufficient to modulate CD19 expression in diffuse large B-cell lymphoma cell lines. Thus, the activity of multiple alternate FOXP1 promoters to produce multiple protein isoforms is likely to regulate B-cell maturation.

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FOXP1 directly represses transcription of proapoptotic genes and cooperates with NF-κB to promote survival of human B cells

Cited by 87 publications

References 74 publications

The forkhead transcription factor FOXP1 represses human plasma cell differentiation

The forkhead transcription factor FOXP1 represses human plasma cell differentiation

The hematopoietic oncoprotein FOXP1 promotes tumor cell survival in diffuse large B-cell lymphoma by repressing S1PR2 signaling

N-terminally truncated FOXP1 protein expression and alternate internal FOXP1 promoter usage in normal and malignant B cells

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