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PARP14 is a Novel Target in STAT6 Mutant Follicular Lymphoma

ABSTRACT: The variable clinical course of follicular lymphoma (FL) is determined by the molecular heterogeneity of tumor cells and complex interactions within the tumor microenvironment (TME). IL-4 producing follicular helper T cells (TFH) are critical components of the FL TME. Binding of IL-4 to IL-4R on FL cells activates JAK/STAT signaling. We identified STAT6 mutations (STAT6MUT) in 13% of FL (N = 33/258), all clustered within the DNA binding domain. Gene expression data and immunohistochemistry showed upregulation of IL-4/STAT6 target genes in STAT6MUT FL, including CCL17, CCL22, and FCER2 (CD23). Functionally, STAT6MUT was gain-of-function by serial replating phenotype in pre-B CFU assays. Expression of STAT6MUT enhanced IL-4 induced FCER2/CD23, CCL17 and CCL22 expression and was associated with nuclear accumulation of pSTAT6. RNA sequencing identified PARP14 -a transcriptional switch and co-activator of STAT6- among the top differentially upregulated genes in IL-4 stimulated STAT6MUT lymphoma cells and in STAT6MUT primary FL cells. Quantitative chromatin immunoprecipitation (qChIP) demonstrated binding of STAT6MUT but not STAT6WT to the PARP14 promotor. Reporter assays showed increased IL-4 induced transactivation activity of STAT6MUT at the PARP14 promotor, suggesting a self-reinforcing regulatory circuit. Knock-down of PARP14 or PARP-inhibition abrogated the STAT6MUT gain-of-function phenotype. Thus, our results identify PARP14 as a novel therapeutic target in STAT6MUT FL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE208031 | GEO | 2022/07/17

REPOSITORIES: GEO

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PARP14 is a Novel Target in STAT6 Mutant Follicular Lymphoma

Project description:PARP14 is a Novel Target in STAT6 Mutant Follicular Lymphoma

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Project description:Prior exposure to certain signals can fundamentally change the response of innate immune cells to other stimuli underpinning phenomena such as cellular memory, tissue type-specific reactions, cytokine storm or anergy/tolerance. Our understanding about the molecular details of such interactions especially at the level of chromatin accessibility and gene expression regulation is fragmented. In particular our knowledge about the molecular links between two fundamental signaling pathways, alternative macrophage polarization signals and TLR signaling pathway is rather limited and neither the epigenomic mechanisms at play nor the biological output is well understood. Here we combined systematic signaling, epigenomic and transcriptomic approaches to map and uncover that the activation of the IL-4-STAT6 signaling pathway results in enhanced LPS responsiveness of a large, but distinct set of genes in macrophages. This interaction, we termed extreme synergy, is brought about by IL-4 priming-induced STAT6-dependent epigenomic remodeling, which includes the expansion of the LPS-activated NFκB-p65 cistrome, increased chromatin accessibility, epigenomic activation and increased enhancer activity at the genomic loci of synergistically activated genes. The IL-4-induced EGR2 transcription factor is required to enable the LPS-induced de novo and enhanced NFκB-p65 binding and synergistic gene activation. As a consequence, the previously alternatively polarized macrophages produce secreted immune-modulatory factors, including CCL17, CCL22, CCL2, and EDN1, at an extremely high level in vitro and in vivo in a murine Th2-type airway inflammation and asthma model following LPS exposure. Our findings establish that the IL-4-STAT6-EGR2 signaling pathway-induced epigenetic reprogramming is responsible for the development of a defined, robust inflammatory hyperresponsiveness to TLR4 activation in alternatively polarized macrophages and likely contribute to pathologies.

2022-10-20 | GSE181223 | GEO

Licensing of PPARg-regulated gene expression by IL-4-induced alternative macrophage activation

Project description:This SuperSeries is composed of the following subset Series: GSE16385: Expression data from human macrophages GSE16386: Expression data from human alternatively activated macrophages GSE25088: PPARg and IL-4-induced gene expression data from wild-type and STAT6 knockout mouse bone marrow-derived macrophages GSE25123: PPARg and IL-4-induced gene expression data from PPARg +/- LysCre and PPARg fl/- LysCre mouse bone marrow-derived macrophages GSE25125: PPARg and IL-4-induced gene expression data from PPARg +/- LysCre and PPARg fl/- LysCre mouse bone marrow-derived alternatively activated macrophages and immature dendritic cells (iDCs) Refer to individual Series

2010-11-18 | E-GEOD-16387 | biostudies-arrayexpress

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Project description:IL-4/STAT6-regulated transcriptome and proteome were compared in primary B cells isolated from wild-type and STAT6-deficient mice. B cells were purified from the spleen and stimulated in vitro with anti-CD40 and LPS or anti-IgM-F(ab)2 in the presence or absence of IL-4. Transcriptome analysis was performed with oligonucleotide microarrays. Global relative quantification of proteins was achieved by gel-enhanced label-free liquid chromatography/mass spectrometry (LC/MS). Hierarchical clustering and principal component analysis revealed that IL-4-induced changes of the transcriptome were almost completely dependent on STAT6. In contrast, the quantitative proteome analysis revealed that the expression of many IL-4-regulated proteins changes even in the absence of STAT6. The top 75 proteins with changes in abundance levels induced by IL-4 in a STAT6-dependent manner were also found to be regulated at the transcriptional level. Most of these proteins were not previously known to be regulated by STAT6 in B cells. We confirmed the MS-based quantitative proteome data by flow cytometric and Western blot analysis of selected proteins. This study provides a framework for further functional characterization of STAT6-regulated proteins in B cells that might be involved in germinal center formation and class switch recombination.

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Follicular B (FoB) cells purified from miR-17-92 tKO mice, stimulated with LPS/IL-4, 13.5hr

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RNA seq data of B cells from naïve, OPN knockout (Spp1-/-), ONKOSCID (SCID Spp1-/-) BALB/c mice

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2021-08-20 | GSE118826 | GEO

tFL with a PMBL GE signature

Project description:We investigated the clinicopathologic features of 5 follicular lymphomas (FL) that transformed to morphologic diffuse large B-cell lymphomas (DLBCL) and had a primary mediastinal large B-cell lymphoma (PMBL)-like gene expression profile. None of the transformed FL (tFL) arose in the mediastinum, all cases tested had a germinal center B-cell immunophenotype, 20% were CD30+, 60% CD23+, 80% MAL+, 20% CD200+, and 0% CD273/PDL2+. Whole exome sequencing detected alterations in genes associated with both FL/DLBCL (CREBBP, KMT2C, KMT2D, ARID1A, HIST1 members, and TNFRSF14) and PMBL (JAK-STAT pathway genes, B2M, and CD58). Copy number (CN) analysis detected gains/amplification of REL in 60% and STAT6 in 40%, gains of chromosome 16, including IL4R, in 40%, and both deletions and gains of 11q in 20%. This cohort, although limited in size, supports a subset of tFL that has blended features between FL/DLBCL and PMBL. Despite having some features that are less common in DLBCL (MAL and CD23 expression, JAK-STAT activation), these cases lack the most characteristic CN alteration seen in PMBL (9p24.1 gain/amplification). This cohort expands the biologic heterogeneity of tFL, illustrating a subset with blended FL/DLBCL and PMBL features, with potential treatment implications that include the use of novel PMBL-targeted therapies.

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2010-06-25 | E-GEOD-17850 | biostudies-arrayexpress

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Project description:To understand the role of LSD1 in splenic B cell development, spleens from mice with B cell conditional deletion of LSD1 were harvested, B220+CD93–GL7–CD23–CD21hiCD1d+ marginal zone B cells and B220+CD93–GL7–CD23+CD21midCD1d– follicular B cells were FACS-sorted, and RNA-seq was performed to identify LSD1-target regulated genes.

2019-08-06 | GSE132197 | GEO

LSD1 regulates splenic B cell chromatin accessibility

Project description:To understand the role of LSD1 in splenic B cell development, spleens from mice with B cell conditional deletion of LSD1 were harvested, B220+CD93–GL7–CD23–CD21hiCD1d+ marginal zone B cells and B220+CD93–GL7–CD23+CD21midCD1d– follicular B cells were FACS-sorted, and ATAC-seq was performed to identify LSD1-target regulated chromatin.

2019-08-06 | GSE132196 | GEO

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