As the first identified selenoprotein, glutathione peroxidase 1 (GPX1) is a widely and abundantly expressed antioxidant enzyme. GPX1 utilizes glutathione as a substrate to catalyze hydrogen peroxide, lipid peroxide, and peroxynitrite, thereby reducing intracellular oxidative stress. The GPX1 gene is regulated at transcriptional, post-transcriptional, and translational levels. Numerous case-control studies and meta-analyses have assessed the association between a functional genetic polymorphism of the GPX1 gene, named Pro198Leu (rs1050450 C>T), and cancer susceptibility in different populations. GPX1 polymorphism has type-specific effects as a candidate marker for cancer risk, but the association between GPX1 variants and cancer susceptibility remains controversial in different studies. GPX1 is abnormally elevated in most types of cancer but has complex dichotomous roles as tumor suppressor and promoter in different cancers. GPX1 can participate in various signaling pathways to regulate tumor biological behaviors, including cell proliferation, apoptosis, invasion, immune response, and chemoresistance. In this review, we comprehensively summarize the controversial associations between GPX1 polymorphism and cancer risks and further discuss the relationships between the aberrant expressions of GPX1 and tumorigenesis. Further studies are needed to elucidate the clinical significance of GPX1 as a potential prognostic biomarker and novel therapeutic target in various malignancies.

The long non-coding RNA H19 plays a crucial role in solid tumor initiation and progression. However, the potential role of H19 and its clinical significance in acute myeloid leukemia (AML) remain largely elusive. H19 expression was detected by qPCR, and clinical significance in AML patients was further analyzed. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data for AML were used as validation cohorts. The roles of H19 in cell proliferation and apoptosis were determined by cell proliferation assay and flow cytometry analysis. H19 expression was significantly increased in AML patients but not associated with embedded miR-675 expression. Moreover, H19 overexpression was not dependent on the methylation pattern in H19 differentially methylated region/imprinting control region. Strong association was observed between H19 overexpression and patients’ characteristics including sex, higher white blood cells, older age, and intermediate karyotype, FLT3-ITD, and DNMT3A mutations. In addition, H19 overexpression correlated with lower complete remission (CR) rate and shorter overall survival, and further confirmed by multivariate analyses. Importantly, the prognostic effect of H19 expression was validated by TCGA and GEO data. In the follow-up of patients, H19 expression in CR phase was lower than diagnosis time and returned at relapse time. Loss-of-function experiments showed that H19 exhibited anti-proliferative and pro-apoptotic effects in leukemic cell HL60. Furthermore, H19 expression was positively correlated with potential downstream gene ID2 in AML. Our findings revealed that methylation-independent H19 was a prognostic and predictive biomarker in AML, and H19/ID2 played crucial roles in leukemogenesis with potential therapeutic target value.

Background: Altered expression of the BCL-2 family member MCL-1 has been linked to the progression and outcome of various malignancies. Recently, MCL-1 inhibitor S63845 was reported to kill MCL-1-dependent cancer cells and has potential value in clinical application. Purpose: Herein, we reported MCL-1 expression pattern in Chinese de novo acute myeloid leukemia (AML) and its impact on prognosis and may provide theoretical basis for AML patients using MCL-1 inhibitor in clinics. Real-time quantitative PCR was carried out to detect the transcript of MCL-1 in AML patients. Results: MCL-1 expression was significantly up-regulated in AML compared with controls (P=0.042). We divided the patients into two groups (higher and lower expression of MCL-1) based on the median level. Among both non-acute promyelocytic leukemia (APL) and cytogenetically normal AML (CN-AML), patients with higher expression of MCL-1 correlated with lower complete remission (CR) rate (P=0.031 and 0.004, respectively) and shorter overall survival (OS) time (P=0.008 and 0.004, respectively) compared with those with lower expression of MCL-1. Meanwhile, Cox regression analyses revealed that overexpression of MCL-1 acted as an independent risk factor for OS in non-APL patients and CN-AML patients (P=0.011 and 0.045, respectively). In follow-up patients, MCL-1 expression level decreased after CR compared with newly diagnosis time (P=0.020) and increased after relapse (P=0.004). Conclusion: Our findings suggest that higher expression of MCL-1 predicts poor prognosis and can be used for disease monitoring.

Background and purpose: Abundant studies have shown that lncRNA PANDAR plays an oncogenic role in human solid tumors. Although abnormal expression of PANDAR has been well investigated in solid tumors, it was rarely studied in hematologic diseases. Hence, the aim of this study was to determine the PANDAR expression level and its clinical significance in patients with acute myeloid leukemia (AML). Materials and methods: For detecting the expression level of PANDAR in 119 AML patients and 26 controls, real-time quantitative PCR was used in this study. The prognostic values were evaluated by using Kaplan–Meier analysis, Cox regression analyses, and logistic regression analysis. Results: PANDAR was significantly overexpressed in AML and might be a promising biomarker which could distinguish AML from normal samples (P<0.001). Patients with high expression of PANDAR (PANDAR^high) were older and showed higher bone marrow blasts than patients in PANDAR^low group (P=0.029 and 0.032, respectively). Significant differences between these groups were also detected regarding risk group and karyotype finding (P=0.009 and 0.041, respectively). Importantly, PANDAR^high patients presented a significant lower complete remission rate compared to PANDAR^low patients (P<0.001). Furthermore, Kaplan–Meier analysis showed that PANDAR^high patients had shorter overall survival compared to PANDAR^low patients observing the whole AML cohort, and also in the non-M3 group of patients (P<0.001 and P=0.005, respectively). Multivariate analysis of Cox and logistic regression analysis confirmed that high PANDAR expression was an independent unfavorable risk factor for overall survival and complete remission in both observed patient groups. Conclusion: These results revealed that PANDAR was overexpressed in AML, and that higher PANDAR expression was associated with poor clinical outcome. Our study therefore suggests that PANDAR expression is a promising biomarker for prognostic prediction for AML.

The deregulated DLX gene family members DLX1/2/3/4/5/6 (DLXs) caused by DNA methylation has been demonstrated in various cancers with therapeutic target value. However, the potential role of DLXs methylation in myeloid neoplasms such as acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) remains to be elucidated. Clinical significance of DLXs methylation/expression was analyzed in patient with AML and MDS. The functional roles of DLXs were determined in vitro. In the identification stage, we found that lower DLX5 expression was correlated with prognosis in AML among all DLXs analyzed by The Cancer Genome Atlas datasets. In the validation stage, we revealed that reduced DLX5 expression was frequently occurred, and was also correlated with promoter hypermethylation in AML evaluated by targeted bisulfite sequencing. Epigenetic studies also showed that DLX5 promoter DNA methylation was associated with its expression. By quantitative polymerase chain reaction, we also validated that DLX5 hypermethylation was frequent event in both AML and MDS, and also correlated with MDS transformation to leukemia. Moreover, DLX5 hypermethylation was associated with lower rate of complete remission and shorter time of leukemia‐free/overall survival, and was also confirmed by Logistic/Cox regression analysis. Functional studies revealed the antiproliferative and pro‐apoptotic effects of DLX5 in MDS‐derived AML cell‐line SKM‐1. Finally, bioinformatics analysis demonstrated that DLX5 functioned in leukemogenesis may be through the association with PI3K/Akt signaling pathway. Collectively, our findings demonstrated that DLX5 methylation, negatively correlated DLX5 expression, was a potential prognostic and predictive indicator in patients with AML and MDS, which could also act as an epigenetic driver in myeloid neoplasms.

DNA methyltransferases (DNMTs) by regulating DNA methylation play crucial roles in the progression of hematologic malignancies, especially for acute myeloid leukemia (AML). Accumulating investigations have identified the high incidence of DNMT3A mutation in AML, and it is correlated with poor prognosis. Although a few studies have shown the expression of DNMTs and their clinical significance in AML, the results remain to be discussed. Herein, we systemically analyzed the DNMTs expression and their relationship with clinic-pathological features and prognosis in AML patients. DNMTs expression especially for DNMT3A/3B was closely associated with AML among various human cancers. DNMT3A expression was increased in AML patients, whereas DNMT3B expression was decreased. Significant associations between DNMT3A/B expression and clinic-pathological features/gene mutations were observed. Kaplan-Meier analysis showed that DNMT3A expression was associated with better overall survival (OS) and leukemia-free survival (LFS) among whole-cohort AML, and independently affected OS determined by Cox repression multivariate analysis. Notably, patients that received hematopoietic stem cell transplantation (HSCT) showed significantly better OS and LFS in DNMT3A lower-expressed groups, whereas patients in DNMT3A higher-expressed groups did not. By bioinformatics analysis, DNMT3A expression was found to be positively correlated with several leukemia-associated genes/microRNAs, and DNMT3A was identified as direct targets of miR-429 and miR-29b in AML. Collectively, our study demonstrated that DNMT3A/3B showed significant expression differences in AML. DNMT3A expression acted as a potential prognostic biomarker and may guide treatment choice between chemotherapy and HSCT in AML.