PD-1 and PD-L1 gene expressions and their association with Epstein-Barr virus infection in chronic lymphocytic leukemia

PurposeThe PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligand, programmed cell death ligand-1 (PD-L1), is expressed on the surface of dendritic cells or macrophages. The PD-1/PD-L1 interaction ensures prevention of autoimmunity by activating the immune system only when needed. In cancers, PD-L1 expressed on the tumour cells binds to PD-1 receptors on the activated T cells, leading to inhibition of the cytotoxic T cells and immunosuppression. PD-1/PD-L1 pathway is upregulated in EBV infection that is known to worsen the CLL prognosis. Therefore, we aimed to study the association between PD-1 and PD-L1 expressions, EBV status and the CLL prognosis.Methods and patientsThe study was conducted on 80 newly diagnosed CLL patients and 80 controls. We analyzed PD-1 and PD-L1 expressions and EBV-DNA load by real-time PCR. The cytogenetic abnormalities and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively.ResultsPD-1/PD-L1 expressions were significantly upregulated in CLL patients compared to controls. In addition, their mRNA levels were significantly higher in EBV( +) versus EBV( −) patients. High expression of PD-1/PD-L1 was associated with poor prognostic markers (RAI stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression-free survival, and overall survival.ConclusionHigh expression of PD-1 and PD-L1, together with high EBD-DNA load were linked to worse prognosis in CLL. In addition, PD-1 and PD-L1 might represent suitable therapeutic targets for patients suffering from aggressive CLL. (AU)

PD-1 and PD-L1 gene expressions and their association with Epstein-Barr virus infection in chronic lymphocytic leukemia.

PURPOSE: The  PD-1 (programmed cell death-1) receptor is expressed on the surface of activated T cells. Its ligand, programmed cell death ligand-1 (PD-L1), is expressed on the surface of dendritic cells or macrophages. The PD-1/PD-L1 interaction ensures prevention of autoimmunity by activating the immune system only when needed. In cancers, PD-L1 expressed on the tumour cells binds to PD-1 receptors on the activated T cells, leading to inhibition of the cytotoxic T cells and immunosuppression. PD-1/PD-L1 pathway is upregulated in EBV infection that is known to worsen the CLL prognosis. Therefore, we aimed to study the association between PD-1 and PD-L1 expressions, EBV status and the CLL prognosis. METHODS AND PATIENTS: The study was conducted on 80 newly diagnosed CLL patients and 80 controls. We analyzed PD-1 and PD-L1 expressions and EBV-DNA load by real-time PCR. The cytogenetic abnormalities and expression of ZAP70 and CD38 were detected by FISH and Flow cytometry, respectively. RESULTS: PD-1/PD-L1 expressions were significantly upregulated in CLL patients compared to controls. In addition, their mRNA levels were significantly higher in EBV( +) versus EBV( -) patients. High expression of PD-1/PD-L1 was associated with poor prognostic markers (RAI stages of CLL, del 17p13, ZAP70, and CD38 expression), failure of complete remission, shorter progression-free survival, and overall survival. CONCLUSION: High expression of PD-1 and PD-L1, together with high EBD-DNA load were linked to worse prognosis in CLL. In addition, PD-1 and PD-L1 might represent suitable therapeutic targets for patients suffering from aggressive CLL.

The clinical significance of the alternative Wilms tumor gene overexpression-hypermethylation signature in acute myeloid leukemia.

BACKGROUND: Wilms tumor 1 (WT1) gene is overexpressed in numerous cancers, including acute myeloid leukemia (AML). The alternative WT1 gene (AWT1) is generated from alternative transcription start site in the WT1 first intron and encodes an N-terminal-truncated protein lacking the repressor domain. Although WT1 overexpression is a common feature in AML, the expression levels of the AWT1 and its underlying epigenetic alterations, as well as their clinical relevance in AML remain unknown. METHODS: Quantitative assessment of AWT1 gene transcripts was performed using real-time polymerase chain reaction (PCR). Bisulfite PCR followed by pyrosequencing was done to determine the methylation status of the AWT1 promoter. The bone marrow samples were collected at diagnosis and after completion of induction chemotherapy from 80 newly diagnosed AML patients. Forty non-malignant BM samples were recruited as controls. RESULTS: The AWT1 was significantly overexpressed in AML patients. Robust hypermethylation of the AWT1 promoter was found to be a highly specific and sensitive marker for AML (p < 0.001). Significant positive correlations between the AWT1 expression and methylation levels with BM blast counts at both initial diagnosis and after induction therapy were observed (p < 0.001). AWT1 overexpression at the initial diagnosis of AML was found to be an independent negative factor for complete remission response after induction therapy (p = 0.014). CONCLUSION: The AWT1 gene overexpression-hypermethylation signature is a characteristic marker that positively correlates with the leukemic burden in AML. AWT1 overexpression at AML diagnosis is an independent negative predictor for CR after induction chemotherapy.