Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-{kappa}B pathways in subtypes of diffuse large B-cell lymphoma.
The activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor-kappaB (NF-kappaB) pathway. In this study, we showed that the NF-kappaB 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-kappaB 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-kappaB signaling. These findings suggest that the biological interplay between the STAT3 and NF-kappaB pathways may be exploited for the treatments of a subset of ABC DLBCLs.
Lam
Lloyd T
LT
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Wright
George
G
Davis
R Eric
RE
Lenz
Georg
G
Farinha
Pedro
P
Dang
Lenny
L
Chan
John W
JW
Rosenwald
Andreas
A
Gascoyne
Randy D
RD
Staudt
Louis M
LM
D019898:Autocrine Communication / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000235:genetics; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
C508609:IL10 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D053612:Janus Kinases