Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Whole genome mapping of STAT3 binding sites in the two major subtypes of diffuse large B cell lymphoma

ABSTRACT: 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.)

ORGANISM(S): Homo sapiens

SUBMITTER: Jennifer Hardee

PROVIDER: E-GEOD-50723 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

STAT3 targets suggest mechanisms of aggressive tumorigenesis in diffuse large B-cell lymphoma.

Hardee Jennifer J Ouyang Zhengqing Z Zhang Yuping Y Kundaje Anshul A Lacroute Philippe P Snyder Michael M

G3 (Bethesda, Md.) 20131209 12

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 thera ...[more]

PMID: 24142927

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Project description:The activated B cell-like (ABC) subgroup of diffuse large B cell lymphoma (DLBCL) is characterized by constitutive activation of the NF-ÃªB pathway. Here we show that the NF- ÃªB pathway induces the expression of the cytokines IL-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated STAT3 protein, suggesting autocrine signaling. Using RNA interference for STAT3, we defined a gene expression signature of IL-6 and IL-10 signaling through STAT3. Based on this signature, we constructed a molecular predictor of STAT3 signaling that defined a subset of ABC DLBCL tumors with high expression of STAT3, IL-6 and/or IL-10, and their downstream targets. Although the STAT3-high and STAT3-low subsets had equivalent expression of genes that distinguish ABC DLBCL from GCB DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-kB activity, proliferation, and glycolysis. A smallmolecule inhibitor of JAK signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines, and synergized with an inhibitor of NF-kB signaling. These findings suggest that the biological interplay between the STAT3 and NF-kB pathways may be exploited for the treatments of a subset of ABC DLBCLs. Activated B cell-like (ABC) subgroup of diffuse large B cell lymphoma (DLBCL) cell lines were used as model systems to study the cytokine pathways in these cells. We expressed inducible IkB super-repressor for 1 to 24 hours to identify NF-kB target genes in OCI-Ly3 and OCI-Ly10 cells for a total of 13 arrays with replicates of each time point. We treated OCI-Ly3 cells with IL-10 for 1 to 96 hours for a total of 10 arrays with replicates of each time point. We treated OCI-Ly10 cells with IL-6 for 30 minutes to 24 hours for a total of 8 arrays with replicates of each time point. OCI-Ly10 cells transfected with no siRNA versus STAT3-siRNA for 8, 24, or 48 hours for a total of 5 arrays with replicates for 24 and 48 hours. We treated OCI-Ly10 cells with JAK inhibitor I for 3 and 6 hours for a total of 4 arrays with replicates of each time point.

Dataset Information

Whole genome mapping of STAT3 binding sites in the two major subtypes of diffuse large B cell lymphoma

Publications

STAT3 targets suggest mechanisms of aggressive tumorigenesis in diffuse large B-cell lymphoma.

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