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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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Downstream pathways and genes induced by STAT3 in ABC DLBCL. Examples of the top GO Biological Processes categories enriched among genes with increased expression and increased STAT3 binding in ABC DLBCL. All P-values are corrected for multiple comparisons using the Benjamini-Hochberg procedure.
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fig10: Downstream pathways and genes induced by STAT3 in ABC DLBCL. Examples of the top GO Biological Processes categories enriched among genes with increased expression and increased STAT3 binding in ABC DLBCL. All P-values are corrected for multiple comparisons using the Benjamini-Hochberg procedure.

Mentions: The combination of whole-genome profiling approaches shows differential STAT3 binding sites near almost a third of all genes that differ in expression between GCB and ABC DLBCL, leaving little doubt that STAT3 is a regulator of the aggressive clinical phenotype and drug resistance displayed by the ABC subtype. The STAT3 binding and expression results suggest possible models by which STAT3 regulates biological pathways to promote aggressive oncogenic behavior in ABC DLBCL. Ontological analysis of the genes up-regulated in ABC DLBCL with increased nearby STAT3 binding indicates that STAT3 promotes cell migration, blood vessel development, and the inflammatory response (Figure 10). Furthermore, it ensures its own continued high expression by up-regulating its pathway partners and upstream signaling molecules, such as IL-6 and IL-10, and promotes cross-talk with the nuclear factor-κB pathway. Most critically, STAT3 strongly up-regulates many mechanisms of apoptosis resistance. These effects synergize and likely lead to increased cell proliferation and distributions of cells, which are hallmarks of aggressive lymphomas. These results provide novel insights into the genetics of oncogenesis in the ABC form of diffuse large B-cell lymphoma and identify a substantial number of plausible downstream mechanisms for the treatment-resistant phenotype of this subtype.


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)

Downstream pathways and genes induced by STAT3 in ABC DLBCL. Examples of the top GO Biological Processes categories enriched among genes with increased expression and increased STAT3 binding in ABC DLBCL. All P-values are corrected for multiple comparisons using the Benjamini-Hochberg procedure.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig10: Downstream pathways and genes induced by STAT3 in ABC DLBCL. Examples of the top GO Biological Processes categories enriched among genes with increased expression and increased STAT3 binding in ABC DLBCL. All P-values are corrected for multiple comparisons using the Benjamini-Hochberg procedure.
Mentions: The combination of whole-genome profiling approaches shows differential STAT3 binding sites near almost a third of all genes that differ in expression between GCB and ABC DLBCL, leaving little doubt that STAT3 is a regulator of the aggressive clinical phenotype and drug resistance displayed by the ABC subtype. The STAT3 binding and expression results suggest possible models by which STAT3 regulates biological pathways to promote aggressive oncogenic behavior in ABC DLBCL. Ontological analysis of the genes up-regulated in ABC DLBCL with increased nearby STAT3 binding indicates that STAT3 promotes cell migration, blood vessel development, and the inflammatory response (Figure 10). Furthermore, it ensures its own continued high expression by up-regulating its pathway partners and upstream signaling molecules, such as IL-6 and IL-10, and promotes cross-talk with the nuclear factor-κB pathway. Most critically, STAT3 strongly up-regulates many mechanisms of apoptosis resistance. These effects synergize and likely lead to increased cell proliferation and distributions of cells, which are hallmarks of aggressive lymphomas. These results provide novel insights into the genetics of oncogenesis in the ABC form of diffuse large B-cell lymphoma and identify a substantial number of plausible downstream mechanisms for the treatment-resistant phenotype of this subtype.

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