期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 3, 页码 E498-E505出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1715118115
关键词
STAT3; interferon; diffuse large B cell lymphoma
资金
- University of Wisconsin, Madison
- KL2 Scholar Award [UL1TR0000427, KL2TR000428]
- National Cancer Institute [1R01 CA187299]
- University of Wisconsin, Madison, T32 Hematology Training Award [T32 HL07899]
- University of Wisconsin Forward Lymphoma Fund
- Intramural Research Program of the National Cancer Institute
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-kappa B, 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.
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