Correlation between STAT3 binding presence and gene expression levels in subtypes of diffuse large B cell lymphoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE50724 | GEO | 2013/12/16
SECONDARY ACCESSION(S): PRJNA218583
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-12-16 | E-GEOD-50724 | biostudies-arrayexpress
Project description:Correlation between STAT3 binding presence and gene expression levels in subtypes of diffuse large B cell lymphoma
| PRJNA218583 | ENA
Project description:The goal of this study is to identify the effect of the transcription factor STAT3 in the two major subtypes of diffuse large B cell lymphoma (DLBCL). STAT3 is a signal transducer that, when dysregulated, becomes a powerful oncogene found in many human cancers, including DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma and has two major subtypes: germinal center B-cell-like (GCB) and activated B-cell-like (ABC). When compared to the GCB form, ABC lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have used ChIP-Seq to identify STAT3 binding sites in 8 DLBCL cell lines (4 GCB subtype, 4 ABC) that are derived from patient tumors. 10,337 distinct STAT3 binding regions are occupied in at least two of the eight cell lines. One third (n = 3524) are differentially bound by STAT3 between the two subtypes (FDR < 0.05). More BRs are strongly bound in ABC than in GCB: 44% of differentially bound BRs (n = 1550) show more STAT3 binding in GCB, while 56% (n = 1974) are more strongly bound in ABC. Identification and comparison of STAT3 transcription factor binding sites in 8 cell lines that represent the 2 subtypes of DLBCL. 4 cell lines are subtyped as ABC and 4 are subtyped as GCB. 2-9 replicates and 1 input control are present for each cell line. (Cell line OCI-Ly19 was not included in the final analysis because RNA-Seq showed that its gene expression clustered in between the subtypes, probably due to its EBV+ status. However, its peak calls were used in intermediate steps of the analysis pipeline. Its sequencing runs have been included for completeness.)
2013-12-16 | E-GEOD-50723 | biostudies-arrayexpress
Project description:The goal of this study is to identify the effect of the transcription factor STAT3 in the two major subtypes of diffuse large B cell lymphoma (DLBCL). STAT3 is a signal transducer that, when dysregulated, becomes a powerful oncogene found in many human cancers, including DLBCL. DLBCL is the most common form of non-Hodgkin’s lymphoma and has two major subtypes: germinal center B-cell-like (GCB) and activated B-cell-like (ABC). When compared to the GCB form, ABC lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have used ChIP-Seq to identify STAT3 binding sites in 8 DLBCL cell lines (4 GCB subtype, 4 ABC) that are derived from patient tumors. 10,337 distinct STAT3 binding regions are occupied in at least two of the eight cell lines. One third (n = 3524) are differentially bound by STAT3 between the two subtypes (FDR < 0.05). More BRs are strongly bound in ABC than in GCB: 44% of differentially bound BRs (n = 1550) show more STAT3 binding in GCB, while 56% (n = 1974) are more strongly bound in ABC.
2013-12-16 | GSE50723 | GEO
Project description:Persistent STAT3 activation has been found in activated B-cell like diffuse large B cell tumors (DLBCL). To investigate whether genetic mutations play a role in aberrant STAT3 signaling in DLBCL, we bi-directionally sequenced all 24 exons of the STAT3 gene in DLBCL tumors (n?=?40). We identified 2 novel point mutations in 2 separate (2/40; 5%) patients at exon 7 and 24. Point mutation 2552G>A was a silent mutation in the stop codon. Another heterozygous mutation 857T>A encoded a methionine substitution by lysine at codon 206 (M206K) in the coiled-coil domain of STAT3. We performed site directed mutagenesis to mutate wild type (WT) STAT3? and STAT3? at codon 206 and constructed stable cell lines by lentiviral transfection of STAT3?(WT), STAT3?(M206K), STAT3?(WT) and STAT3?(M206K) plasmids. The mutation was found to increase STAT3 phosphorylation in STAT3? mutant cell lines with no effect on the STAT3? mutant cell line. Transcriptional activation was also increased in the STAT3? mutant cells compared with STAT3? WT cells as detected by a luciferase reporter assay. Moreover, STAT3?(M206K) mutant cells were resistant to JAK2 pathway inhibition compared to STAT3? WT cells. These results indicate that missense mutations in STAT3 increase signaling through the JAK/STAT pathway. JAK2 inhibitors may be useful in the patient with this STAT3 mutation as well as those with pathway activation by other mechanisms.
| S-EPMC3701620 | biostudies-literature
Project description:Expression profiling has shown 2 main and clinically distinct subtypes of diffuse large B-cell lymphomas (DLBCLs): germinal-center B cell-like (GCB) and activated B cell-like (ABC) DLBCLs. Further work has shown that these subtypes are partially characterized by distinct genetic alterations and different survival. Here, we show with the use of an assay that measures DNA methylation levels of 50,000 CpG motifs distributed among more than 14,000 promoters that these 2 DLBCL subtypes are also characterized by distinct epigenetic profiles. DNA methylation and gene expression profiling were performed on a cohort of 69 patients with DLBCL. After assigning ABC or GCB labels with a Bayesian expression classifier trained on an independent dataset, a supervised analysis identified 311 differentially methylated probe sets (263 unique genes) between ABC and GCB DLBCLs. Integrated analysis of methylation and gene expression showed a core tumor necrosis factor-? signaling pathway as the principal differentially perturbed gene network. Sixteen genes overlapped between the core ABC/GCB methylation and expression signatures and encoded important proteins such as IKZF1. This reduced gene set was an accurate predictor of ABC and GCB subtypes. Collectively, the data suggest that epigenetic patterning contributes to the ABC and GCB DLBCL phenotypes and could serve as useful biomarker.
| S-EPMC2993635 | biostudies-literature
Project description:The signal transducer and activator of transcription 3 (STAT3) is a transcription factor that, when dysregulated, becomes a powerful oncogene found in many human cancers, including diffuse large B-cell lymphoma. Diffuse large B-cell lymphoma is the most common form of non-Hodgkin's lymphoma and has two major subtypes: germinal center B-cell-like and activated B-cell-like. Compared with the germinal center B-cell-like form, activated B-cell-like lymphomas respond much more poorly to current therapies and often exhibit overexpression or overactivation of STAT3. To investigate how STAT3 might contribute to this aggressive phenotype, we have integrated genome-wide studies of STAT3 DNA binding using chromatin immunoprecipitation-sequencing with whole-transcriptome profiling using RNA-sequencing. STAT3 binding sites are present near almost a third of all genes that differ in expression between the two subtypes, and examination of the affected genes identified previously undetected and clinically significant pathways downstream of STAT3 that drive oncogenesis. Novel treatments aimed at these pathways may increase the survivability of activated B-cell-like diffuse large B-cell lymphoma.
| S-EPMC3852380 | biostudies-literature
Project description:JMJD3 (Jumonji domain containing-3), a histone H3 Lys27 (H3K27) demethylase, has been reported to be involved in the antigen-driven differentiation of germinal center B-cells. However, insight into the mechanism of JMJD3 in DLBCL (Diffuse large B-cell lymphoma) progression remains poorly understood. In this study, we investigated the subtype-specific JMJD3-dependent survival effects in DLBCL. Our data showed that in the ABC subtype, silencing-down of JMJD3 inhibited interferon regulatory factor 4 (IRF4) expression in a demethylase activity-dependent fashion. IRF4 reciprocally stimulated expression of JMJD3, forming a positive feedback loop that promoted survival in these cells. Accordingly, IRF4 expression was sufficient to rescue the pro-apoptotic effect of JMJD3 suppression in the ABC, but not in the GCB subtype. In contrast, ectopic overexpression of BCL-2 completely offset JMJD3-mediated survival in the GCB DLBCL cells. In vivo, treatment with siRNA to JMJD3 reduced tumor volume concordant with increased apoptosis in either subtype. This suggests it is a common target, though the distinctive signaling axes regulating DCBCL survival offer different strategic options for treating DLBCL subtypes.
| S-EPMC5045403 | biostudies-literature
Project description:Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways.
| S-EPMC2533222 | biostudies-literature
Project description:Suppressor of cytokine signaling 1 (SOCS1) is frequently mutated in primary mediastinal and diffuse large B-cell lymphomas (DLBCL). Currently, the prognostic relevance of these mutations in DLBCL is unknown. To evaluate the value of the SOCS1 mutation status as a prognostic biomarker in DLBCL patients, we performed full-length SOCS1 sequencing in tumors of 154 comprehensively characterized DLBCL patients. We identified 90 SOCS1 mutations in 16% of lymphomas. With respect to molecular consequences of mutations, we defined two distinct subtypes: those with truncating (major) and those with non-truncating mutations (minor), respectively. The SOCS1 mutated subgroup or the minor/major subtypes cannot be predicted on clinical grounds; however, assignment of four established gene-expression profile-based classifiers revealed significant associations of SOCS1 major cases with germinal center and specific pathway activation pattern signatures. Above all, SOCS1 major cases have an excellent overall survival, even better than the GCB-like subgroup. SOCS1 minor cases had a dismal survival, even worse than the ABC gene signature group. The SOCS1 mutation subsets retained prognostic significance in uni- and multivariate analyses. Together our data indicate that assessment of the SOCS1 mutation status is a single gene prognostic biomarker in DLBCL.
| S-EPMC3702206 | biostudies-other