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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3701-3713.
Prepublished online as a Blood First Edition Paper on January 2, 2008; DOI 10.1182/blood-2007-09-111948.
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NEOPLASIA
Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor- B pathways in subtypes of diffuse large B-cell lymphoma
Lloyd T. Lam1,
George Wright2,
R. Eric Davis1,
Georg Lenz1,
Pedro Farinha3,
Lenny Dang4,
John W. Chan5,
Andreas Rosenwald6,
Randy D. Gascoyne3, and
Louis M. Staudt1
1 Metabolism Branch, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD;
2 Biometric Research Branch, NCI, Rockville, MD;
3 British Columbia Cancer Agency, Vancouver, BC;
4 Millennium Pharmaceuticals, Cambridge, MA;
5 Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha; and
6 Department of Pathology, University of Würzburg, Würzburg, Germany
The activated B cell–like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor- B (NF-B) pathway. In this study, we showed that the NF-B 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-B 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-B signaling. These findings suggest that the biological interplay between the STAT3 and NF-B pathways may be exploited for the treatments of a subset of ABC DLBCLs.
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