The Effect of NPL4-Targeted Inhibitor Disulfiram on the Expression of Genes Related to the Ubiquitin-Proteasome Pathway in T-Cell Malignancies

Objective Our previous studies have demonstrated that disulfiram (DSF) exerts antitumor effects on T-cell malignancies, including T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoma (TCL), through the ubiquitin-proteasome pathway mediated by nuclear protein localization protein 4 homolog (NPL4). This study aims to investigate the regulatory effects of disulfiram on the expression of genes related to the ubiquitin-proteasome pathway in T-cell malignancies, providing a basis for precision targeted therapy of T-cell malignancies.

Methods Jurkat cells, a T-ALL cell line, were treated with 0.4 μM disulfiram for 48 hours. Transcriptome sequencing was performed to analyze differentially expressed genes, and real-time quantitative PCR was used to validate the relative expression levels of these genes in 10 T-cell malignancy samples (GZFPH dataset). Additionally, transcriptome sequencing data from 262 cases of T-ALL and 140 cases of TCL were downloaded from the TARGET and GSE58445 databases for survival analysis.

Results  After treating Jurkat cells with 0.4 μM disulfiram for 48 hours, 86 genes were downregulated and 35 genes were upregulated in the ubiquitin-proteasome pathway. Among these genes, univariate Cox regression and survival curve analysis revealed that only low expression of ubiquitin-conjugating enzyme E2 J1 (UBE2J1) was associated with poor prognosis in patients with T-ALL and TCL in both the TARGET and GSE58445 datasets (P < 0.05). When incorporating UBE2J1 expression level, age, and gender into univariate and multivariate Cox regression analyses, low expression of UBE2J1 emerged as an independent prognostic factor for patients with T-ALL and TCL (P < 0.05).

Conclusions  Disulfiram can regulate the expression of the UBE2J1 gene, and its low expression is associated with poor prognosis in patients with T-cell malignancies. This study provides a theoretical basis for further elucidating the antitumor effects of disulfiram and the potential use of UBE2J1 as a biomarker for risk stratification in T-cell malignancies.