The forkhead transcription factor FOXP1 represses human plasma cell differentiation

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

doi:10.1182/blood-2015-02-626176

Cited by 44 publications

(40 citation statements)

References 55 publications

(60 reference statements)

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“…However, IgM + MBCs were also enriched for many genes proposed to regulate or inhibit B cell activation, such as FCRLA, FCRL2, FCRL3, CBLB, CD72 and SIGLEC10 (Wu and Bondada, 2009, Sohn et al, 2003, Meyer et al, 2018, Kochi et al, 2009, Shabani et al, 2014), which may reflect a fine regulatory balance controlling their activation threshold. Perhaps underpinning this, unswitched MBCs also expressed higher levels of the transcription factor genes POU2F2 (OCT2) and FOXP1 than class-switched MBCs (Figure 5F), which coordinate the capacity of B cells to respond normally to antigen receptor signals and directly repress key regulators of plasma cell differentiation respectively (van Keimpema et al, 2015, Corcoran et al, 2014). This is consistent with switched IgG + MBCs being more likely to differentiate into plasma cells, while unswitched IgM + MBCs are more likely to re-enter or form secondary GC responses to gain higher affinity (Dogan et al, 2009, Lutz et al, 2015, Seifert et al, 2015).…”

Section: Resultsmentioning

confidence: 96%

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

King

Orban

Riches

et al. 2020

Preprint

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15In response to antigen challenge, B cells clonally expand, undergo selection and differentiate to produce 16 mature B cell subsets and high affinity antibodies. However, the interplay between dynamic B cell states 17 and their antibody-based selection is challenging to decipher in primary human tissue. We have applied 18 an integrated analysis of bulk and single-cell antibody repertoires paired with single-cell transcriptomics 19 of human B cells undergoing affinity maturation. We define unique gene expression and antibody 20 repertoires of known and novel B cell states, including a pre-germinal centre state primed to undergo 21 class switch recombination. We dissect antibody class-dependent gene expression of germinal centre 22 and memory B cells to find that class switching prior to germinal centre entry dictates the capacity of B 23 cells to undergo antibody-based selection and differentiate. Together, our analyses provide 24 unprecedented resolution into the gene expression and selection dynamics that shape B cell-mediated 25 immunity. 26 27 121 122 157 sampling of IgH sequences from bulk repertoires to enhance genotype correction, identification of 158

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Section: Resultsmentioning

confidence: 96%

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

King

Orban

Riches

et al. 2020

Preprint

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“…30 For microarray analysis, after transduction cells were cultured without cytokines for three days.…”

Section: Methodsmentioning

confidence: 99%

The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells

et al. 2016

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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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“…Like all forkhead factors, FOXP1 is a multifaceted transcription factor responsible for fine-tuning the spatial and temporal expression of a broad range of genes both during development and in adult tissues. 22 In hematopoietic cells, FOXP1 contributes to differentiation of immature B cells and plasmocytes 31,32 ; it enforces naive T-cell quiescence by limiting cell cycle progression. 33,34 It also inhibits differentiation of monocytes to macrophages.…”

Section: Discussionmentioning

confidence: 99%

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

Naudin

Hattabi

Michelet

et al. 2017

Blood

103

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Key Points• The RNA regulators PUMILIO sustain HSPC and acute myeloid leukemia cell growth by upregulating FOXP1 expression through direct binding to 2 FOXP1-39UTR PUMILIO-binding elements.• FOXP1 mediates PUMILIO growth-promoting activities by repressing expression of p21 CIP1 and p27 KIP1 cell cycle inhibitors.RNA-binding proteins (RBPs) have emerged as important regulators of invertebrate adult stem cells, but their activities remain poorly appreciated in mammals. Using a short hairpin RNA strategy, we demonstrate here that the 2 mammalian RBPs, PUMILIO (PUM)1 and PUM2, members of the PUF family of posttranscriptional regulators, are essential for hematopoietic stem/progenitor cell (HSPC) proliferation and survival in vitro and in vivo upon reconstitution assays. Moreover, we found that PUM1/2 sustain myeloid leukemic cell growth. Through a proteomic approach, we identified the FOXP1 transcription factor as a new target of PUM1/2. Contrary to its canonical repressive activity, PUM1/2 rather promote FOXP1 expression by a direct binding to 2 canonical PUM responsive elements present in the FOXP1-39 untranslated region (UTR). Expression of FOXP1 strongly correlates with PUM1 and PUM2 levels in primary HSPCs and myeloid leukemia cells. We demonstrate that FOXP1 by itself supports HSPC and leukemic cell growth, thus mimicking PUM activities. Mechanistically, FOXP1 represses the expression of the p212CIP1 and p27 2KIP1 cell cycle inhibitors. Enforced FOXP1 expression reverses shPUM antiproliferative and proapoptotic activities. Altogether, our results reveal a novel regulatory pathway, underscoring a previously unknown and interconnected key role of PUM1/2 and FOXP1 in regulating normal HSPC and leukemic cell growth. (Blood. 2017;129(18):2493-2506

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The forkhead transcription factor FOXP1 represses human plasma cell differentiation

Cited by 44 publications

References 55 publications

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

Antibody repertoire and gene expression dynamics of diverse human B cell states during affinity maturation

The small FOXP1 isoform predominantly expressed in activated B cell-like diffuse large B-cell lymphoma and full-length FOXP1 exert similar oncogenic and transcriptional activity in human B cells

PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells

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