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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, 2008December 26, 2007; DOI 10.1182/blood-2007-09-111948.
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Submitted September 12, 2007
Accepted December 18, 2007
Cooperative signaling through the STAT3 and NF- B pathways in subtypes of diffuse large B cell lymphoma
Lloyd T. Lam, George Wright, R. Eric Davis, Georg Lenz, Pedro Farinha, Lenny Dang, John W. Chan, Andreas Rosenwald, Randy Gascoyne, and Louis M Staudt*
Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Biometric Research Branch, National Cancer Institute, Rockville, MD, United States
Department of Pathology and Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Oncology Biochemistry, Millennium Pharmaceuticals, Cambridge, MA, United States
Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
Department of Pathology, University of Wuerzburg, Wuerzburg, Germany
* Corresponding author; email: lstaudt{at}mail.nih.gov.
The activated B cell-like (ABC) subgroup of diffuse large B cell lymphoma (DLBCL) is characterized by constitutive activation of the NF- B pathway. Here we show that the NF-B pathway induces the expression of the cytokines IL-6 and IL-10 in ABC DLBCL cell lines, which also have high levels of total and phosphorylated STAT3 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 GCB DLBCL, STAT3-high ABC DLBCLs had higher expression of signatures that reflected NF-B activity, proliferation, and glycolysis. A small-molecule inhibitor of JAK 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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