Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma

LT Lam, G Wright, RE Davis, G Lenz… - Blood, The Journal …, 2008 - ashpublications.org
LT Lam, G Wright, RE Davis, G Lenz, P Farinha, L Dang, JW Chan, A Rosenwald…
Blood, The Journal of the American Society of Hematology, 2008ashpublications.org
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 …
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.
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