Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy, however, specific tumor-associated genes and signaling pathways are yet to be deciphered. Differentially expressed genes (DEGs) were computed based on gene expression profiles from GSE32018, GSE56315, and The Cancer Genome Atlas (TCGA) DLBC. Overlapping DEGs were then evaluated for gene ontology (GO), pathways enrichment, DNA methylation, protein–protein interaction (PPI) network analysis as well as survival analysis. Seventy-four up-regulated and 79 down-regulated DEGs were identified. From PPI network analysis, majority of the DEGs were involved in cell cycle, oocyte meiosis, and epithelial-to-mesenchymal transition (EMT) pathways. Six hub genes including CDC20, MELK, PBK, prostaglandin D2 synthase (PTGDS), PCNA, and CDK1 were selected using the Molecular Complex Detection (MCODE). CDC20 and PTGDS were able to predict overall survival (OS) in TCGA DLBC and in an additional independent cohort GSE31312. Furthermore, CDC20 DNA methylation negatively regulated CDC20 expression and was able to predict OS in DLBCL. A two-gene panel consisting of CDC20 and PTGDS had a better prognostic value compared with CDC20 or PTGDS alone in the TCGA cohort (P=0.026 and 0.039). Overall, the present study identified a set of novel genes and pathways that may play a significant role in the initiation and progression of DLBCL. In addition, CDC20 and PTGDS will provide useful guidance for therapeutic applications.
Background Chronic lymphocytic leukemia (CLL) results in increased susceptibility to infections. T cell dysfunction is not associated with CLL in all patients; therefore, it is important to identify CLL patients with T cell defects. The role of B-cell lymphoma-2 (BCL-2) in CLL has been explored; however, few studies have examined its role in T cells in CLL patients. Herein, we have investigated the regulatory role of BCL-2 in T cells in the CLL tumor microenvironment. Methods The expression of BCL-2 in T cells was evaluated using flow cytometry. The regulatory roles of BCL-2 were investigated using single-cell RNA sequencing (scRNA-seq) and verified using multi-parameter flow cytometry on CD4 and CD8 T cells. The clinical features of BCL-2 expression in T cells in CLL were also explored. Results We found a significant increase in BCL-2 expression in the T cells of CLL patients (n = 266). Single cell RNA sequencing (scRNA-seq) indicated that BCL-2+CD4+ T cells had the gene signature of increased regulatory T cells (Treg); BCL-2+CD8+ T cells showed the gene signature of exhausted cytotoxic T lymphocytes (CTL); and increased expression of BCL-2 was associated with T cell activation and cellular adhesion. The results from scRNA-seq were verified in peripheral T cells from 70 patients with CLL, wherein BCL-2+CD4+ T cells were enriched with Tregs and had higher expression of interleukin-10 and transforming growth factor-β than BCL-2−CD4+ T cells. BCL-2 expression in CD8+T cells was associated with exhausted cells (PD-1+Tim-3+) and weak expression of granzyme B and perforin. T cell–associated cytokine profiling revealed a negative association between BCL-2+ T cells and T cell activation. Decreased frequencies and recovery functions of BCL-2+T cells were observed in CLL patients in complete remission after treatment with venetoclax. Conclusion BCL-2 expression in the T cells of CLL patients is associated with immunosuppression via promotion of Treg abundance and CTL exhaustion.
Background Bone marrow mesenchymal stem cell (BM-MSC) has been shown to treat pulmonary arterial hypertension (PAH). However, excessive reactive oxygen species (ROS) increases the apoptosis of BM-MSCs, leading to poor survival and engraft efficiency. Thus, improving the ability of BM-MSCs to scavenge ROS may considerably enhance the effectiveness of transplantation therapy. Mammalian Ste20-like kinase 1 (Mst1) is a pro-apoptotic molecule which increases ROS production. The aim of this study is to uncover the underlying mechanisms the effect of Mst1 inhibition on the tolerance of BM-MSCs under H2O2 condition. Methods Mst1 expression in BM-MSCs was inhibited via transfection with adenoviruses expressing a short hairpin (sh) RNA directed against Mst1 (Ad-sh-Mst1) and exposure to H2O2. Cell viability was detected by Cell Counting Kit 8 (CCK-8) assay, and cell apoptosis was analyzed by Annexin V-FITC/PI, Caspase 3 Activity Assay kits, and pro caspase 3 expression. ROS level was evaluated by the ROS probe DCFH-DA, mitochondrial membrane potential (ΔΨm) assay, SOD1/2, CAT, and GPx expression. Autophagy was assessed using transmission electron microscopy, stubRFP-sensGFP-LC3 lentivirus, and autophagy-related protein expression. The autophagy/Keap1/Nrf2 signal in H2O2-treated BM-MSC/sh-Mst1 was also measured. Results Mst1 inhibition reduced ROS production; increased antioxidant enzyme SOD1/2, CAT, and GPx expression; maintained ΔΨm; and alleviated cell apoptosis in H2O2-treated BM-MSCs. In addition, this phenomenon was closely correlated with the autophagy/Keap1/Nrf2 signal pathway. Moreover, the antioxidant pathway Keap1/Nrf2 was also blocked when autophagy was inhibited by the autophagy inhibitor 3-MA. However, Keap1 or Nrf2 knockout via siRNA had no effect on autophagy activation or suppression. Conclusion Mst1 inhibition mediated the cytoprotective action of mBM-MSCs against H2O2-induced oxidative stress injury. The underlying mechanisms involve autophagy activation and the Keap1/Nrf2 signal pathway. Graphical abstract
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