BackgroundThe 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.MethodsH19 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.ResultsH19 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0486-z) contains supplementary material, which is available to authorized users.

Promoter hypermethylation-mediated inactivation of ID4 plays a crucial role in the development of solid tumours. This study aimed to investigate ID4 methylation and its clinical relevance in myeloid malignancies. ID4 hypermethylation was associated with higher IPSS scores, but was not an independent prognostic biomarker affecting overall survival (OS) in myelodysplastic syndrome (MDS). However, ID4 hypermethylation correlated with shorter OS and leukaemia-free survival (LFS) time and acted as an independent risk factor affecting OS in acute myeloid leukaemia (AML). Moreover, ID4 methylation was significantly decreased in the follow-up paired AML patients who achieved complete remission (CR) after induction therapy. Importantly, ID4 methylation was increased during MDS progression to AML and chronic phase (CP) progression to blast crisis (BC) in chronic myeloid leukaemia (CML). Epigenetic studies showed that ID4 methylation might be one of the mechanisms silencing ID4 expression in myeloid leukaemia. Functional studies in vitro showed that restoration of ID4 expression could inhibit cell proliferation and promote apoptosis in both K562 and HL60 cells. These findings indicate that ID4 acts as a tumour suppressor in myeloid malignancies, and ID4 methylation is a potential biomarker in predicting disease progression and treatment outcome.

Background BCL2 protein inhibitor venetoclax (ABT-199) has been authorized by Food and Drug Administration for relapsed/refractory chronic lymphoid leukemia with 17p deletion. Although venetoclax/ABT-199 also caused cell death in acute myeloid leukemia (AML), whether it could be applied to clinical treatment needs further studies. Here, we revealed clinical implication of BCL2 overexpression in de novo adult AML, and may provide theoretical basis for targeted therapy using venetoclax. Methods BCL2 expression was analyzed in adult AML patients from public datasets The Cancer Genome Atlas (TCGA) and confirmed by another independent cohort from our own data. Results BCL2 expression showed up-regulated in AML patients among TCGA data and confirmed by our own data. BCL2 overexpression was correlated with FAB-M0/M1, whereas BCL2 under-expression was related to FAB-M5. However, BCL2 expression has no effect on overall survival (OS) and leukemia-free survival (LFS) of AML patients (determined in BCL2 low and BCL2 high groups). Interestingly, in the BCL2 low group, patients undergoing autologous or allogeneic hematopoietic stem cell transplantation (auto/allo-HSCT) had significantly better OS and LFS compared with patients only received chemotherapy, whereas, no significant difference was found in OS and LFS between chemotherapy and auto/allo-HSCT patients in the BCL2 high group. BCL2 expression was found positively correlated with HOX family gene, and negatively correlated with tumor suppressor microRNA such as miR-195 , miR-497 , and miR-193b . Conclusions BCL2 overexpression identified specific FAB subtypes of AML, but it did not affect prognosis. Patients with BCL2 overexpression did not benefit from auto/allo-HSCT among whole-cohort-AML and cytogenetically normal AML. Electronic supplementary material The online version of this article (10.1186/s13000-019-0841-1) contains supplementary material, which is available to authorized users.

13C NMR spectra and relaxation parameters (T 1 H, T 1 C, T 1 ρ H, T CH) were measured via CP-MAS and DP-MAS techniques as a function of acetone loading level in acetone/SiO2 samples at 25 °C. T 1 H and T 1 ρ H values were also measured via 29Si CP-MAS experiments. Peak positions and relaxation parameters are averaged by rapid exchange between different acetone interaction sites on the surface. The data were analyzed in terms of a surface equilibrium of adsorbed acetone units between hydrogen-bonding and non-hydrogen-bonding sites. Data analysis by this model yielded the surface concentration of hydrogen-bonding (silanol) sites (1.5 nm-2) and the equilibrium constant (K = 3.0 nm2). Variable-temperature experiments (124−297 K) at three loading levels yielded values of ΔH° (−5.8 ± 0.3 kJ mol-1) and ΔS° (−12.5 ± 0.7 J K-1 mol-1). A self-consistent, qualitative interpretation of measured relaxation parameters is made in terms of the relative mobilities of hydrogen-bonded (less mobile) and non-hydrogen-bonded (more mobile) acetone on the SiO2 surface.

Chemoresistance is one of the causes associated with poor prognosis in gastric cancer. MicroRNAs (miRNAs) are important regulators of chemoresistance. Exosome-mediated delivery of anti-cancer molecules and drugs have emerged as a new approach for cancer therapy. We first examined the expression of miR-374a-5p in gastric cancer serum by qRT-PCR and explored the clinicopathological parameters. We then performed in vitro cell and molecular studies, including CCK-8 assay, flow cytometry, qRT-PCR, and western blot, to determine the roles of miR-374a-5p in gastric cancer chemoresistance and identified its downstream target by luciferase reporter assay. We also used in vivo animal studies to evaluate the therapeutic efficacy of miR-374a-5p inhibitor and exosome-mediated delivery of miR-374a-5p inhibitor in gastric cancer. miR-374a-5p expression level was elevated in gastric cancer serum, and its upregulation predicted poor prognosis. miR-374a-5p overexpression promoted while miR-374a-5p knockdown inhibited gastric cancer chemoresistance in vitro and in vivo. miR-374a-5p bound to Neurod1 to antagonize its effect on chemoresistance. Exosome-mediated delivery of miR-374a-5p inhibitor could increase Neurod1 expression, promote cell apoptosis, and suppress chemoresistance. miR-374a-5p had a promoting role in gastric cancer chemoresistance, which would provide a novel biomarker for gastric cancer diagnosis and prognosis and offer a potential target for gastric cancer drug resistance therapy.

Elderly patients with acute myeloid leukemia (AML) have limited treatment options concerned about their overall fitness and potential treatment related mortality. Although a number of clinical trials demonstrated benefits of decitabine treatment in elderly AML patients, the results remains controversial. A meta-analysis was performed to evaluate efficacy and safety of decitabine in treatment of elderly AML patients. Eligible studies were identified from PubMed, Web of Science, Embase and Cochrane Library. Nine published studies were included in the meta-analysis, enrolling 718 elderly AML patients. The efficacy outcomes were complete remission (CR), overall response rate (ORR) and overall survival (OS). Safety was evaluated based on treatment related grades 3–4 adverse events (AEs) and early death (ED) rate. Pooled estimates with 95% confidence interval (CI) for CR, ORR and OS were 27% (95% CI 19%–36%), 37% (95% CI 28%–47%) and 8.09 months (95% CI 5.77–10.41), respectively. The estimated treatment related early death (ED) incidences were within 30-days 7% (95% CI 2%–11%) and 60-days 17% (95% CI 11%–22%), respectively. Thrombocytopenia was the most common grades 3–4 AEs. Subgroup analyses of age, cytogenetics risk, AML type and bone marrow blast percentage showed no significant differences of treatment response to decitabine. In conclusion, decitabine is an effective and well-tolerated therapeutic alternative with acceptable side effects in elderly AML patients.

BackgroundMethylation-associated SOX family genes have been proved to be involved in multiple essential processes during carcinogenesis and act as potential biomarkers for cancer diagnosis, staging, prediction of prognosis, and monitoring of response to therapy. Herein, we revealed SOX30 methylation and its clinical implication in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).ResultsIn the discovery stage, we identified that SOX30 methylation, a frequent event in AML, was negatively associated with SOX30 expression and correlated with overall survival (OS) and leukemia-free survival (LFS) in cytogenetically normal AML among SOX family members from The Cancer Genome Atlas (TCGA) datasets. In the validation stage, we verified that SOX30 methylation level was significantly higher in AML even in MDS-derived AML compared to controls, whereas SOX30 hypermethylation was not a frequent event in MDS. SOX30 methylation was inversely correlated with SOX30 expression in AML patients. Survival analysis showed that SOX30 hypermethylation was negatively associated with complete remission (CR), OS, and LFS in AML, where it only affected LFS in MDS. Notably, among MDS/AML paired patients, SOX30 methylation level was significantly increased in AML stage than in MDS stage. In addition, SOX30 methylation was found to be significantly decreased in AML achieved CR when compared to diagnosis time and markedly increased in relapsed AML when compared to the CR population.ConclusionsOur findings revealed that SOX30 methylation was associated with disease progression in MDS and acted as an independent prognostic and predictive biomarker in AML.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0523-y) contains supplementary material, which is available to authorized users.

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.