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Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma
- Source :
- PubMed Central
- Publication Year :
- 2008
- Publisher :
- American Society of Hematology, 2008.
-
Abstract
- The activated B cell–like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor-κB (NF-κB) pathway. In this study, we showed that the NF-κB pathway induced the expression of the cytokines interleukin (IL)-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated signal transducer and activator of transcription (STAT) 3 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 germinal center B cell–like DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-κB activity, proliferation, and glycolysis. A small-molecule inhibitor of Janus kinase signaling, which blocked STAT3 signature expression, was toxic only for ABC DLBCL lines and synergized with an inhibitor of NF-κB signaling. These findings suggest that the biological interplay between the STAT3 and NF-κB pathways may be exploited for the treatments of a subset of ABC DLBCLs.
- Subjects :
- STAT3 Transcription Factor
Immunology
Biochemistry
Cell Line, Tumor
hemic and lymphatic diseases
medicine
Humans
Autocrine signalling
STAT3
Protein Kinase Inhibitors
Cell Proliferation
Janus Kinases
biology
Neoplasia
Gene Expression Regulation, Leukemic
Interleukin-6
NF-kappa B
Germinal center
Cell Biology
Hematology
medicine.disease
Interleukin-10
Autocrine Communication
Cancer research
biology.protein
STAT protein
RNA Interference
Lymphoma, Large B-Cell, Diffuse
Signal transduction
Janus kinase
Glycolysis
Diffuse large B-cell lymphoma
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- PubMed Central
- Accession number :
- edsair.doi.dedup.....178c8e5a041e21e009170c1ff5602dfa