期刊
BLOOD ADVANCES
卷 3, 期 8, 页码 1255-1266出版社
ELSEVIER
DOI: 10.1182/bloodadvances.2018025973
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资金
- National Institutes of Health, National Cancer Institute [R01CA165469, R01CA197844, R01CA159296, R35CA197734]
- D. Warren Brown Foundation
- Four Winds Foundation
- Sullivan Chronic Lymphocytic Leukemia Research Fund
- Connie Brown CLL Foundation
- [P30CA016058]
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 x 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 x TCL1 and TCL1 individuals, indicating delayed but pathologically normal disease progression in Par-4 x 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 x TCL1 mice compared with TCL1 littermates. Moreover, reduced nuclear p65 levels were observed in Par-4 x TCL1 splenic B cells compared with TCL1, suggesting suppressed NF-kappa B signaling. These findings have identified an in vivo antileukemic role for Par-4 through an NF-kappa B-dependent mechanism in TCL1-mediated CLL-like disease progression.
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