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

  1. Author:
    Lu, Li
    Zhu, Fen
    Zhang, Meili
    Li, Yangguang
    Drennan, Amanda C
    Kimpara, Shuichi
    Rumball, Ian
    Selzer, Christopher
    Cameron, Hunter
    Kellicut, Ashley
    Kelm, Amanda
    Wang, Fangyu
    Waldmann, Thomas A
    Rui, Lixin

  2. Author Address

    Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792., Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792., Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892., Laboratory Animal Science Program, Leidos Biomedical Research, Inc., Frederick, MD 21702., Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; tawald@mail.nih.gov lrui@medicine.wisc.edu., Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792; tawald@mail.nih.gov lrui@medicine.wisc.edu.,
    1. Year: 2018
    2. Date: Jan 16
    3. Epub Date: 2018 01 02
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 115
    2. 3
    3. Pages: E498-E505
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. 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-?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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External Sources

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  2. DOI: 10.1073/pnas.1715118115
  3. PMID: 29295936
  4. View record in Web of Science®
  5. WOS: 000423091400020
  6. PII : 1715118115

Library Notes

  1. Fiscal Year: FY2017-2018
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