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

Hardee J, Ouyang Z, Zhang Y, Kundaje A, Lacroute P, Snyder M - G3 (Bethesda) (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305.

ABSTRACT
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.

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ChIP-Seq BR enrichment for ontological categories. Scale is the –log10(P-value) of the binomial P-value, equivalent to the exponent. (A) All enriched GO Biological Processes, P < 0.05. (B) All enriched PANTHER Pathways, P < 0.05. (C) All enriched Disease Ontology listings, P < 0.05. Data shown for ABC only, as GCB had no significantly enriched categories.
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fig4: ChIP-Seq BR enrichment for ontological categories. Scale is the –log10(P-value) of the binomial P-value, equivalent to the exponent. (A) All enriched GO Biological Processes, P < 0.05. (B) All enriched PANTHER Pathways, P < 0.05. (C) All enriched Disease Ontology listings, P < 0.05. Data shown for ABC only, as GCB had no significantly enriched categories.

Mentions: The Gene Ontology Biological Processes (GO BP) ontology shows that STAT3 BRs occupied in ABC DLBCL are located near genes involved in B-cell activation and mature B-cell differentiation (Figure 4A). This result is consistent with STAT3’s role in B-cell maturation and with the theory that more mature B-cells give rise to the ABC subtype (Angelin-Duclos et al. 2000; Falini et al. 2000; Fornek et al. 2006; Avery et al. 2010). The Disease Ontology analysis reveals that the 1974 ABC-enriched STAT3 BRs fall near genes associated with many forms of cancer, especially lymphomas and leukemias (Figure 4C).


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

Hardee J, Ouyang Z, Zhang Y, Kundaje A, Lacroute P, Snyder M - G3 (Bethesda) (2013)

ChIP-Seq BR enrichment for ontological categories. Scale is the –log10(P-value) of the binomial P-value, equivalent to the exponent. (A) All enriched GO Biological Processes, P < 0.05. (B) All enriched PANTHER Pathways, P < 0.05. (C) All enriched Disease Ontology listings, P < 0.05. Data shown for ABC only, as GCB had no significantly enriched categories.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3852380&req=5

fig4: ChIP-Seq BR enrichment for ontological categories. Scale is the –log10(P-value) of the binomial P-value, equivalent to the exponent. (A) All enriched GO Biological Processes, P < 0.05. (B) All enriched PANTHER Pathways, P < 0.05. (C) All enriched Disease Ontology listings, P < 0.05. Data shown for ABC only, as GCB had no significantly enriched categories.
Mentions: The Gene Ontology Biological Processes (GO BP) ontology shows that STAT3 BRs occupied in ABC DLBCL are located near genes involved in B-cell activation and mature B-cell differentiation (Figure 4A). This result is consistent with STAT3’s role in B-cell maturation and with the theory that more mature B-cells give rise to the ABC subtype (Angelin-Duclos et al. 2000; Falini et al. 2000; Fornek et al. 2006; Avery et al. 2010). The Disease Ontology analysis reveals that the 1974 ABC-enriched STAT3 BRs fall near genes associated with many forms of cancer, especially lymphomas and leukemias (Figure 4C).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, California 94305.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus