We have previously reported aberrant activation of the signal transducer and activator of transcription 3 (STAT3) pathway promotes cell proliferation and survival in the activated B-cell-like (ABC) subtype, but not in the germinal center B-cell-like (GCB) subtype of diffuse large B-cell lymphoma (DLBCL). Herein, we investigated the effects of small molecular inhibitors of STAT3 in sensitizing DLBCL cell to chemotherapy drugs. ABC-DLBCL lines Ly3 and Pfeiffer were more resistant to vincristine-induced cell death than GCB-DLBCL cells Ly1 and Ly7 were. In ABC-DLBCL cells, constitutive activation of STAT3 provided survival signal and inhibited vincristine-induced apoptosis, while inhibition of STAT3 signaling abrogated IL-6 secretion and promoted cell apoptosis. STAT3 inhibitor and chemotherapy drugs synergistically induced cell apoptosis, with increased caspases 3/7 activity and PARP cleavage, in ABC-DLBCL cells but not in the GCB-DLBCL cells. The effect was correlated with reduced expression of MCL1 in these cells. To investigate the prognostic significance of STAT3 activation in DLBCL patients, we evaluated the levels of phospho-Tyr705-STAT3 (PY-STAT3) expression by immunohistochemistry in a cohort of 309 DLBCL patients treated with R-CHOP regimen. The ABC-DLBCL subgroup had significantly higher number of PY-STAT3 positive cases compared to the GCB subgroup (59.4% vs 36.2%; P = 0.003). Constitutive activation of STAT3 pathway has a significant impact on the overall-survival (OS) and event-free-survival (EFS) in the entire DLBCL cohort (OS, P = 0.010; EFS, P = 0.006) and in the ABC subgroup (OS, P = 0.062; EFS, P=0.016). Moreover, we constructed a subgroup of genes representing STAT3 activation from the gene expression profiling data of STAT3-siRNA treated ABC cell lines and primary DLBCL samples. Attributions of these genes include repression with the STAT3 knockdown in DLBCL cell lines, overexpression in the PY-STAT3-positive DLBCL tumors, and containing one or more STAT3 binding motif within their promoter regions. Eleven genes were obtained when trained this gene subgroup with patient survival through a semi-supervised algorithm. Averaged expression of the eleven genes predicted the OS (P < 0.001) and EFS (P < 0.001) in the entire DLBCL cohort, as well as in the ABC-DLBCL subgroup (OS, P = 0.029; EFS, P = 0.025). In conclusion, our study demonstrated that STAT3 activation is a significant prognostic factor in DLBCL and suggested that STAT3 may be a new therapeutic target in this aggressive malignancy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5568. doi:1538-7445.AM2012-5568