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      Stress‐induced premature senescence activated by the  SENEX gene mediates apoptosis resistance of diffuse large B‐cell lymphoma via promoting immunosuppressive cells and cytokines

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          Abstract

          Background

          The underlying cause of relapsed and refractory (r/r) diffuse large B‐cell lymphoma (DLBCL) is usually related to apoptosis resistance to antitumor drugs. The recent years have provided lots of evidence that tumor cells may undergo stress‐induced premature senescence (SIPS) in response to chemotherapy, but how SIPS affects lymphoma cells remains inconclusive.

          Methods

          Fifty‐two DLBCL patients, including 6 newly diagnosed (ND), 17 complete remissions (CR), and 29 (r/r), were enrolled in this study. We used a senescence‐associated‐β‐galactosidase (SA‐β‐Gal) staining kit for senescence staining. Suppressive immune cells including regulatory T cells (Treg) and myeloid‐derived suppressor cells (MDSC) were detected by flow cytometry (FCM). Secreted cytokines were measured by ELISA Kit and SENEX gene expression was detected by a quantitative real‐time polymerase chain reaction. We used 40 nM doxorubicin to induce the SIPS model of DLBCL in vitro. Apoptosis and proliferation activity of senescent LY8 cells were respectively detected by FCM and CCK8. SENEX gene was silenced by RNA interference.

          Results

          The proportion of senescent lymphoma cells was significantly increased in r/r DLBCL patients, concomitant with increased Treg, MDSC, and various secreted cytokines with proinflammatory and immunosuppressive effects. The  SENEX gene was significantly elevated in the SIPS model. Senescent DLBCL cells had good antiapoptotic ability and proliferative activity accompanied by increased immunosuppressive cytokines. Interestingly, when we silenced the  SENEX gene in the DLBCL cell line, the results were the opposite to the above.

          Conclusion

          SIPS activated by the  SENEX gene mediates apoptosis resistance of r/r DLBCL via promoting immunosuppressive cells and cytokines.

          Abstract

          We propose premature senescence induced by the SENEX gene mediates apoptosis resistance of large B‐cell lymphoma (DLBCL) via promoting immunosuppressive cells and cytokines.

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          Most cited references35

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          The senescence-associated secretory phenotype: the dark side of tumor suppression.

          Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.
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            The serial cultivation of human diploid cell strains.

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              Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.

              Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.
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                Author and article information

                Contributors
                zzzm889@163.com
                Journal
                Immun Inflamm Dis
                Immun Inflamm Dis
                10.1002/(ISSN)2050-4527
                IID3
                Immunity, Inflammation and Disease
                John Wiley and Sons Inc. (Hoboken )
                2050-4527
                04 October 2020
                December 2020
                : 8
                : 4 ( doiID: 10.1002/iid3.v8.4 )
                : 672-683
                Affiliations
                [ 1 ] Department of Hematology The Second Affiliated Hospital of Anhui Medical University Hefei Anhui China
                [ 2 ] Department of Hematology, Jingzhou Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei China
                Author notes
                [*] [* ] Correspondence Zhimin Zhai, Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601 Anhui, China.

                Email: zzzm889@ 123456163.com

                Author information
                http://orcid.org/0000-0002-8989-7808
                Article
                IID3356
                10.1002/iid3.356
                7654415
                33015970
                75644bd1-e93e-4cc3-b626-4992f4583327
                © 2020 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 July 2020
                : 04 September 2020
                : 17 September 2020
                Page count
                Figures: 6, Tables: 3, Pages: 12, Words: 5594
                Funding
                Funded by: Research Fund Project of Anhui Medical University , open-funder-registry 10.13039/501100002947;
                Award ID: 2018xkj026
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81670179
                Funded by: National Natural Science Foundation Incubation Project of the Second Hospital of Anhui Medical University
                Award ID: 2019GQFY11
                Funded by: Provincial Natural Science Research Key Project of Anhui Higher Education Institutions
                Award ID: KJ2019A0254
                Categories
                Original Research
                Original Research
                Custom metadata
                2.0
                December 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.3 mode:remove_FC converted:10.11.2020

                dlbcl,immunosuppressive cells,sasp,senex gene,stress‐induced premature senescence

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