Par-4 overexpression impedes leukemogenesis in the Eµ-TCL1 leukemia model through downregulation of NF-κB signaling
| العنوان: | Par-4 overexpression impedes leukemogenesis in the Eµ-TCL1 leukemia model through downregulation of NF-κB signaling |
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| المؤلفون: | John C. Byrd, Frank Frissora, Kevan Zapolnik, Xiaokui Mo, Mary K. McKenna, Minh Tran, Rahul Ramaswamy, Vivek M. Rangnekar, Rajeswaran Mani, Ronni Wasmuth, Bonnie K. Harrington, Subbarao Bondada, Joseph T. Greene, Natarajan Muthusamy, Max Yano |
| المصدر: | Blood Advances. 3:1255-1266 |
| بيانات النشر: | American Society of Hematology, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Genetically modified mouse, Programmed cell death, Carcinogenesis, Chronic lymphocytic leukemia, Mice, Transgenic, Spleen, Pathogenesis, Mice, Proto-Oncogene Proteins, medicine, Animals, Humans, Lymphoid Neoplasia, Chemistry, Tumor Suppressor Proteins, Neoplasms, Experimental, Hematology, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, medicine.anatomical_structure, Cancer research, Bone marrow, CD5, Apoptosis Regulatory Proteins, Signal Transduction |
| الوصف: | Prostate apoptosis response 4 (Par-4) is a tumor suppressor that prevents proliferation and induces cell death in several solid tumors. However, its role in B-cell malignancies has not been elucidated. To describe the role of Par-4 in chronic lymphocytic leukemia (CLL) pathogenesis, we developed a B-cell–specific human Par-4–overexpressing mouse model of CLL using the TCL1 leukemia model. While Par-4 transgenic mice did not display any obvious defects in B-cell development or function, disease burden as evidenced by abundance of CD19+CD5+ B cells in the peripheral blood was significantly reduced in Par-4 × TCL1 mice compared with TCL1 littermates. This conferred a survival advantage on the Par-4–overexpressing mice. In addition, a B-cell–specific knockout model displayed the opposite effect, where lack of Par-4 expression resulted in accelerated disease progression and abbreviated survival in the TCL1 model. Histological and flow cytometry–based analysis of spleen and bone marrow upon euthanasia revealed comparable levels of malignant B-cell infiltration in Par-4 × TCL1 and TCL1 individuals, indicating delayed but pathologically normal disease progression in Par-4 × TCL1 mice. In vivo analysis of splenic B-cell proliferation by 5-ethynyl-2-deoxyuridine incorporation indicated >50% decreased expansion of CD19+CD5+ cells in Par-4 × TCL1 mice compared with TCL1 littermates. Moreover, reduced nuclear p65 levels were observed in Par-4 × TCL1 splenic B cells compared with TCL1, suggesting suppressed NF-κB signaling. These findings have identified an in vivo antileukemic role for Par-4 through an NF-κB–dependent mechanism in TCL1-mediated CLL-like disease progression. |
| تدمد: | 2473-9537 2473-9529 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d85969fde6cc8ea316eb713b8c813388 https://doi.org/10.1182/bloodadvances.2018025973 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....d85969fde6cc8ea316eb713b8c813388 |
| قاعدة البيانات: | OpenAIRE |
Full Text via ClinicalKey | تدمد: | 24739537 24739529 |
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