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Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma

Oncogene volume 36, pages 5252–5262 (2017)Cite this article

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Abstract

Primary effusion lymphoma (PEL), which is an aggressive subgroup of B-cell lymphoma associated with Kaposi sarcoma-associated herpes virus/human herpes virus-8, is refractory to the standard treatment, and exhibits a poor survival. Although PU.1 is downregulated in PEL, the potential role of its reduction remains to be elucidated. In this investigation, we analyzed the DNA methylation of PU.1 cis-regulatory elements in PEL and the effect of restoring PU.1 on PEL cells. The mRNA level of PU.1 was downregulated in PEL cells. The methylated promoter and enhancer regions of the PU.1 gene were detected in PEL cells. Suppression of cell growth and apoptosis were caused by the restoration of PU.1 in PEL cells. A microarray analysis revealed that interferon-stimulated genes (ISGs) including pro-apoptotic ISGs were strongly increased in BCBL-1 cells after the induction of PU.1. Reporter assays showed that PU.1 transactivated pro-apoptotic ISG promoters, such as the XAF1, OAS1 and TRAIL promoters. Mutations at the PU.1 binding sequences suppressed its transactivation. We confirmed the binding of PU.1 to the XAF1, OAS1 and TRAIL promoters in a chromatin immunoprecipitation assay. PU.1 suppressed ORF57 activation by inducing IRF7. The reinduction of PU.1 reduced formation of ascites and lymphoma cell infiltration of distant organs in PEL xenograft model mice. Collectively, PU.1 has a role in tumor suppression in PEL and its down-regulation is associated with PEL development. Restoring PU.1 with demethylation agents may be a novel therapeutic approach for PEL.

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Acknowledgements

This work was supported by the Research program on HIV/AIDS (No. 17fk0410208h0002) from the Japan Agency for Medical Research and Development, AMED, and Grants-in-Aid for Science Research (No. 16K08742) from the Ministry of Education, Science, Sports, and Culture of Japan.

Author contributions

HG and RK performed the experiments; HG, RK, EK, YO, KU and SO interpreted experimental data; HK performed the analysis of immunohistochemistry; HG and SO designed the experiments and wrote the manuscript.

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Authors and Affiliations

  1. Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Honjo, Kumamoto, Japan

    H Goto, R Kariya, E Kudo & S Okada

  2. Departments of Hematology, Rheumatology, and Infectious Disease, Kumamoto University Graduate School of Medicine, Honjo, Kumamoto, Japan

    Y Okuno

  3. Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    K Ueda

  4. Department of Pathology, National Institute of Infectious Diseases, Toyama, Shinjuku, Tokyo, Japan

    H Katano

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  1. H Goto
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  2. R Kariya
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Correspondence to S Okada.

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Goto, H., Kariya, R., Kudo, E. et al. Restoring PU.1 induces apoptosis and modulates viral transactivation via interferon-stimulated genes in primary effusion lymphoma. Oncogene 36, 5252–5262 (2017). https://doi.org/10.1038/onc.2017.138

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