Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma
Cooperative signaling through the signal transducer and activator of transcription 3 and nuclear factor-κB pathways in subtypes of diffuse large B-cell lymphoma
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DOI：
10.1182/blood-2007-09-111948
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发表时间：
2008-04-01
期刊：
影响因子：
20.3
通讯作者：
Staudt, Louis M.
中科院分区：
文献类型：
--
作者：
Lam, Lloyd T.;Wright, George;Staudt, Louis M.
The activated B cell-like (ABC) subgroup of diffuse large B-cell lymphoma (DLBCL) is characterized by constitutive activation of the nuclear factor-kappa B (NF-kappa B) pathway. In this study, we showed that the NF-kappa B pathway induced the expression of the cytokines interleukin (IL)-6 and IL-1 0 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-kappa 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-kappa B signaling. These findings suggest that the biological interplay between the STAT3 and NF-kappa B pathways may be exploited for the treatments of a subset of ABC DLBCLs.
