Gene regulation and suppression of type I interferon signaling by STAT3 in diffuse large B cell lymphoma.

Abstract

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.

• Authors: Li Lu, Fen Zhu, Meili Zhang, Yangguang Li, Amanda C Drennan, Shuichi Kimpara, Ian Rumball, Christopher Selzer, Hunter Cameron, Ashley Kellicut, Amanda Kelm, Fangyu Wang, Thomas A Waldmann, Lixin Rui
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 115 Issue 3 Pg. E498-E505 (01 16 2018) ISSN: 1091-6490 [Electronic] United States
• PMID: 29295936 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Immunologic Factors
• Interferon Type I
• Nitriles
• Pyrazoles
• Pyrimidines
• STAT3 Transcription Factor
• STAT3 protein, human
• Thalidomide
• ruxolitinib
• Lenalidomide

Topics

• Cell Differentiation
• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Cell Survival
• Cytokines (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Genome-Wide Association Study
• Humans
• Immunologic Factors (administration & dosage, pharmacology)
• Interferon Type I (genetics, metabolism)
• Lenalidomide
• Lymphoma, Large B-Cell, Diffuse (metabolism)
• Nitriles
• Pyrazoles (administration & dosage, pharmacology)
• Pyrimidines
• STAT3 Transcription Factor (antagonists & inhibitors, genetics, metabolism)
• Signal Transduction (physiology)
• Thalidomide (administration & dosage, analogs & derivatives, pharmacology)