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.

Prostate apoptosis response-4 and tumor suppression: it’s not just about apoptosis anymore

“…Par-4 modulates NF-κB function in a number of different ways. Recently, Par-4 has been shown to down-regulate NF-κB signaling through inhibition of p65 (also known as RelA; a subunit of NF-κB transcription complex) nuclear translocation and impedes leukemogenesis in an in vivo leukemia model 39 (Fig. 2B ).…”

Immunomagnetic B cell isolation as a tool to study blood cell subsets and enrich B cell transcripts

“…The remaining genes had no reported function in B cells; however, they represent promising areas of further investigation, as their significant expression in B cells suggests involvement in functional pathways. Indeed, CCDC50, KMO, PAWR , PEG10, and PLPP5 may play a role in multiple B cell-associated cancers [20][21][22][23][24], and CDCA7L and OSBPL10 may be risk markers in multiple myeloma and diffuse large B cell lymphoma, respectively [25,26]. Additionally, investigation of B cell signature gene expression levels via the Immunological Genome Project (https:// www.…”

Antitumor Efficacy of Arylquin 1 through Dose-Dependent Cytotoxicity, Apoptosis Induction, and Synergy with Radiotherapy in Glioblastoma Models

“…Biomedicines 2024, 12, 907 2 of 13 Standard treatments for GBM include traditional surgery, radiotherapy (RT), and alkylating agent chemotherapy [2]; however, the prognosis remains poor. Advanced age, poor physical condition, and incomplete surgical resection are recognized as adverse prognostic factors [3,4].…”

“…Recent research has shown that normal cells secrete the Par-4 protein, and extracellular Par-4 induces apoptosis in cancer cells specifically through interaction with the 78 kDa glucose-regulated protein (GRP78) on the cell surface [12]. For example, in the Eµ-TCL1 leukemia model, increased Par-4 expression impedes leukemogenesis predominantly by downregulating NF-κB signaling [13]. Furthermore, Par-4 plays a critical role in preventing the invasion and metastasis of cancer cells.…”