Graded Expression of IRF4 Coordinates Isotype Switching with Plasma Cell Differentiation
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: PRJNA99637
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE6337 | GEO | 2006/11/24
SECONDARY ACCESSION(S): PRJNA99637
REPOSITORIES: GEO
Similar Datasets
Project description:Graded Expression of IRF4 Coordinates Isotype Switching with Plasma Cell Differentiation
| PRJNA99637 | ENA
Project description:Background: Germinal center B-cell (GCB) lymphomas are common in children and adults. The prognosis strongly depends on age. Subgroups of GCB-lymphomas are characterized by chromosomal translocations affecting immunoglobulin (IG) loci leading to oncogene deregulation. Methods: Novel IG translocation partners were cloned within the network “Molecular Mechanisms in Malignant Lymphomas” (MMML) by long-distance inverse polymerase chain reaction. Mature aggressive B-cell lymphomas from the MMML as well as pediatric and adult lymphoma trials were analyzed by fluorescence in situ hybridization (FISH) and immunhistochemistry. Data from 438 MMML cases characterized by gene expression profiling were mined. Results: Cloning of unknown IG partners identified a t(6;14)(p25;q32) juxtaposing the IRF4 oncogene with the IGH-locus as novel recurrent aberration in GCB lymphoma. FISH analyses of 427 mature B-cell lymphomas for IRF4 translocations revealed 20 IG/IRF4 positive lymphomas (17 IGH/IRF4, 2 IGL/IRF4, 1 IGΚ/IRF4). IG/IRF4-positive lymphomas were predominantly GCB-type diffuse large B-cell lymphomas (DLBCL) or follicular lymphoma grade 3, shared overexpression of IRF4/MUM1 and BCL6 and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas was different from other subtypes of DLBCL and a classifier for IG/IRF4 positivity containing 27 genes allowed prediction of 3 additional MMML IG/IRF4-positive cases subsequently proven by FISH. IG/IRF4-positivity was associated with a favorable outcome likely due to significant enrichment of IG/IRF4-positive lymphomas in childhood and young adulthood. Conclusions: Our results suggest IRF4 translocations to be primary genetic alterations in a novel molecularly defined subset of GC-derived lymphomas predominantly affecting children. 271 diffuse large B-Cell lymphoma samples were hybridized to HGU133A Affymetrix GeneChips.
2011-06-24 | E-GEOD-22470 | biostudies-arrayexpress
Project description:Background: Germinal center B-cell (GCB) lymphomas are common in children and adults. The prognosis strongly depends on age. Subgroups of GCB-lymphomas are characterized by chromosomal translocations affecting immunoglobulin (IG) loci leading to oncogene deregulation. Methods: Novel IG translocation partners were cloned within the network “Molecular Mechanisms in Malignant Lymphomas” (MMML) by long-distance inverse polymerase chain reaction. Mature aggressive B-cell lymphomas from the MMML as well as pediatric and adult lymphoma trials were analyzed by fluorescence in situ hybridization (FISH) and immunhistochemistry. Data from 438 MMML cases characterized by gene expression profiling were mined. Results: Cloning of unknown IG partners identified a t(6;14)(p25;q32) juxtaposing the IRF4 oncogene with the IGH-locus as novel recurrent aberration in GCB lymphoma. FISH analyses of 427 mature B-cell lymphomas for IRF4 translocations revealed 20 IG/IRF4 positive lymphomas (17 IGH/IRF4, 2 IGL/IRF4, 1 IGΚ/IRF4). IG/IRF4-positive lymphomas were predominantly GCB-type diffuse large B-cell lymphomas (DLBCL) or follicular lymphoma grade 3, shared overexpression of IRF4/MUM1 and BCL6 and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas was different from other subtypes of DLBCL and a classifier for IG/IRF4 positivity containing 27 genes allowed prediction of 3 additional MMML IG/IRF4-positive cases subsequently proven by FISH. IG/IRF4-positivity was associated with a favorable outcome likely due to significant enrichment of IG/IRF4-positive lymphomas in childhood and young adulthood. Conclusions: Our results suggest IRF4 translocations to be primary genetic alterations in a novel molecularly defined subset of GC-derived lymphomas predominantly affecting children.
2011-06-24 | GSE22470 | GEO
Project description:Single cell RNA seq (scRNA-seq) has emerged as a powerful tool to determine the composition of heterogeneous cell states in a tissue. We found that Irf4+/- antigen specific B cells were functionally impaired in affinity maturation. The goal of this study was to determine whether Irf4+/- antigen specific B cells exhibited distinct cellular composition compared to wild type cells. Sequence data from 8360 cells revealed a similar distribution and numbers of cell states between cells of Irf4+/- or Irf4+/+ genotypes.
2021-10-04 | GSE185188 | GEO
Project description:Multiple myeloma (MM) is an incurable malignancy of plasma cells that exploits transcriptional networks driven by IRF4. To discover unique molecular vulnerabilities in MM centered on IRF4, we employ a multi-omics approach integrating functional genomics screening, spatial proteomics, and global chromatin mapping. We find that ARID1A, a member of the SWI/SNF chromatin remodeling complex, is both required for IRF4 expression and functionally associated with IRF4 protein on chromatin. Deletion of Arid1a in activated murine B cells thwarts subsequent plasma cell differentiation by disrupting IRF4-dependent transcriptional networks, therefore defining ARID1A as a novel plasma cell vulnerability. Targeting ARID1A-dependent SWI/SNF activity via SMARCA2/4 inhibition induces a rapid loss of IRF4-target gene expression and quenches global amplification of oncogenic gene expression driven by MYC, resulting in profound toxicity to MM cells. Notably, MM patients with aggressive disease have markers of SWI/SNF activity, and SMARCA2/4 inhibitors retain their activity in immunomodulatory drug (IMiD)-resistant MM cells. To fully harness the potential of these drugs, we use combinatorial drug screens to uncover profound synergistic toxicity between SMARCA2/4 and MEK inhibitors. Thus, targeting SWI/SNF activity potently represses an IRF4-MYC feed forward loop and provides a feasible path to effectively treat this incurable disease.
2024-01-11 | MSV000093842 | MassIVE
Project description:Temporal analysis of B cell activation in vitro using CD40L and IL-2/4/5 cytokines in wild type Irf4+/+ B cells or in mutant Irf4-/- B cells harboring a tet-inducible allele of Irf4. IRF4 expression was restored, or not, in the Irf4-/- background by culturing in the presence of low or high concentrations of doxycycline. The results provide insight in the role of IRF4 expression levels in coordinating different programs of B cell differentiation. Resting mature peripheral primary B cells were enriched from the spleens of Irf4+/+ or Irf4-inducible mice on the Irf4-/- background. We sought to compare gene expression profiles of wild type and Irf4 mutant B cells in response to mitogens that promote the differentiation of the B cells into plasma cells and cells that have undergone class switch recombination. Day 0 samples represent RNA analysis of unstimulated cells, whereas Day 1 and Day 3 samples represent analysis of stimulated cells in culture. For stimulation, cells were cultured with insect cell purified CD40L and IL-2/4/5 cytokines for the indicated days. In the case of doxycycline-mediated rescue of IRF4 expression, doxycycline was added at predefined low and high concentrations that yield low or high numbers of plasma cells, respectively (see Molecular Systems Biology 7:495). Each replicate represents analysis of B cells from an individual mouse. Of the three replicates in each group, two were performed in parallel and one was performed at a different time. All cells were lysed using Trizol and total RNA was purified according to manufacturer's suggestions. The high quality of the RNA was confirmed using Agilent Bioanalyzer 2100 system. 250ng of RNA was then processed into biotinylated cRNA according to standard procedures and used to hybridize to Affymetrix 430 2.0 arrays. Signal intensities were normalized using the D-Chip algorithm (PM-only model) and the output was used to quantify differential gene expression between groups.
2013-05-04 | E-GEOD-46606 | biostudies-arrayexpress
Project description:Temporal analysis of B cell activation in vitro using CD40L and IL-2/4/5 cytokines in wild type Irf4+/+ B cells or in mutant Irf4-/- B cells harboring a tet-inducible allele of Irf4. IRF4 expression was restored, or not, in the Irf4-/- background by culturing in the presence of low or high concentrations of doxycycline. The results provide insight in the role of IRF4 expression levels in coordinating different programs of B cell differentiation.
2013-05-04 | GSE46606 | GEO
Project description:Gene expression profiling (GEP) divides DLBCL according to the cell of origin into GCB, ABC and unclassifiable, exhibiting different mutational profiles. The Hans algorithm, a surrogate of GEP, classifies cases expressing CD10, BCL6 and MUM1 as GCB but it is not clear whether all these cases correspond to GCB-type. Accordingly, LBCL with IRF4 rearrangement usually expresses GCB phenotype (CD10+, BCL6+) together with strong MUM1/IRF4.
2023-06-05 | GSE178417 | GEO
Project description:Variable strengths of T cell receptor (TCR) signaling can produce divergent outcomes for T cell development and function. The mechanisms leading to different outcomes are incompletely understood, but may include distinct activation thresholds for different transcription factors as well as distinct sensitivities among target genes to transcription factors. IRF4 is one transcription factor implicated in responses to variable TCR signal strength. IRF4 expression increases uniformly with increasing TCR signal strength (i.e., analog), but it is unclear how IRF4 induced distinct genes at different levels, rather than different amounts of the same genes. Here, we analyzed global gene expression in TH2 cells and used ChIP-seq to define the relationship between TCR signal strength, enhancer occupancy and transcriptional activity for BATF/IRF4-dependent genes. We show that enhancers exhibit a spectrum of affinity for the BATF/IRF4 ternary complex mediate graded responsiveness of individual genes to increasing TCR signal strength. Differential gene induction by BATF and IRF4 occurs through interaction with enhancer elements of different affinity for BATF/IRF4 complexes. The increased resolution of factor binding site identified using ChIP-exo allowed the identification of a novel AICE2 motif binding BATF/IRF4 with higher affinity and that this may explain the protective role of a single nucleotide polymorphism in the CTLA-4 locus known to decrease the incidence of autoimmune diseases.
2017-03-27 | GSE85173 | GEO
Project description:Transcriptional profiling of T-cells isolated from spleen of IRF4 -/- mice and cultured under Th17 polarizing conditions for 42 hrs compared to cells similarly isolated and cultured from spleen of IRF4 +/- mice. The aim of the study was to identify global misexpression of genes in IRF4 -/- cells and hence identify key pathways regulated by IRF4 during Th17 differentiation. Two-condition experiment, IRF4 -/- vs IRF4 +/- Th17 cells at 42hrs. Biological replicates: 3 for each condition
2012-09-13 | E-GEOD-40726 | biostudies-arrayexpress