Dataset Information


Par-4 overexpression impedes leukemogenesis in the Eµ-TCL1 leukemia model through downregulation of NF-κB signaling.

ABSTRACT: 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.


PROVIDER: S-EPMC6482354 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

Similar Datasets

2014-01-01 | S-EPMC3896194 | BioStudies
2013-01-01 | S-EPMC3700393 | BioStudies
2013-06-04 | E-GEOD-44940 | ArrayExpress
2013-01-01 | S-EPMC3742013 | BioStudies
2006-01-01 | S-EPMC1518806 | BioStudies
2018-01-13 | GSE109121 | GEO
1000-01-01 | S-EPMC3289317 | BioStudies
2018-01-01 | S-EPMC6024641 | BioStudies
2014-09-01 | E-GEOD-60925 | BioStudies
2009-01-01 | S-EPMC2780304 | BioStudies