STAT3 is constitutively activated in many cancers and regulates gene expression to promote cancer cell survival, proliferation, invasion, and migration. In diffuse large B cell lymphoma (DLBCL), activation of STAT3 and its kinase JAK1 is caused by autocrine production of IL-6 and IL-10 in the activated B cell–like subtype (ABC). However, the gene regulatory mechanisms underlying the pathogenesis of this aggressive lymphoma by STAT3 are not well characterized. Here we performed genome-wide analysis and identified 2,251 STAT3 direct target genes, which involve B cell activation, survival, proliferation, differentiation, and migration. Whole-transcriptome profiling revealed that STAT3 acts as both a transcriptional activator and a suppressor, with a comparable number of up- and down-regulated genes. STAT3 regulates multiple oncogenic signaling pathways, including NF-κB, a cell-cycle checkpoint, PI3K/AKT/mTORC1, and STAT3 itself. In addition, STAT3 negatively regulates the lethal type I IFN signaling pathway by inhibiting expression of IRF7, IRF9, STAT1, and STAT2. Inhibition of STAT3 activity by ruxolitinib synergizes with the type I IFN inducer lenalidomide in growth inhibition of ABC DLBCL cells in vitro and in a xenograft mouse model. Therefore, this study provides a mechanistic rationale for clinical trials to evaluate ruxolitinib or a specific JAK1 inhibitor combined with lenalidomide in ABC DLBCL.
Diffuse Large B-cell Lymphoma Arising in a Patient with Neurofibromatosis Type I and in a Patient with Neurofibromatosis Type II