Eukaryotic initiation factor-2, gamma subunit, suppresses proliferation and regulates the cell cycle via the MAPK/ERK signaling pathway in acute myeloid leukemia.

PURPOSE: The expression of eukaryotic translation initiation factor-2 subunit 3 (EIF2S3) in patients with non-small cell lung and colorectal cancer is lower than that in healthy individuals. However, the functions of EIF2S3 remain unclear, and its study in leukemia has not been reported. The article aims to explore the role of EIF2S3 in AML (acute myeloid leukemia) and its underlying mechanism. METHODS: Reverse transcription-quantitative PCR was performed to evaluate the expression levels of EIF2S3, and its association with patient prognosis was determined. Inducible HEL-EIF2S3 and HL-60-EIF2S3 cell lines were established by retrovirus infection. Cellular proliferation and the cell cycle were analyzed using Cell Counting Kit-8 and flow cytometric analyses. Tumorigenic ability was evaluated using xenograft nude mouse model. Gene expression profiles were analyzed in HL-60-EIF2S3 cells by next-generation sequencing, and WB analysis was performed to detect the expression of related proteins. RESULTS: The expression of EIF2S3 in patients with AML was lower than that experiencing CR (P = 0.02). Furthermore, EIF2S3 overexpression inhibited cellular proliferation, halted G0/1 to S phase cell cycle progression, and inhibited tumorigenicity (P = 0.015). 479 differentially expressed genes were identified between HL60-EIF2S3 DOX (-) and HL60-EIF2S3 DOX ( +) cells via NGS and several of them involved in MAPK/ERK signaling pathway. The phosphorylation levels of ERK decreased when EIF2S3 was overexpressed (P < 0.050). CONCLUSION: EIF2S3 overexpression may result in a decrease in cellular proliferation, cell cycle arrest, and tumorigenic inhibition via the MAPK/ERK signaling pathway in AML cells.

MicroRNA-363-3p promote the development of acute myeloid leukemia with RUNX1 mutation by targeting SPRYD4 and FNDC3B.

BACKGROUND: Runt-related transcription factor 1 (RUNX1) is one of the most frequently mutated genes in most of hematological malignancies, especially in acute myeloid leukemia. In the present study, we aimed to identify the key genes and microRNAs based on acute myeloid leukemia with RUNX1 mutation. The newly finding targeted genes and microRNA associated with RUNX1 may benefit to the clinical treatment in acute myeloid leukemia. MATERIAL/METHODS: The gene and miRNA expression data sets relating to RUNX1 mutation and wild-type adult acute myeloid leukemia (AML) patients were downloaded from The Cancer Genome Atlas database. Differentially expressed miRNAs and differentially expressed genes (DEGs) were identified by edgeR of R platform. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed by Metascape and Gene set enrichment analysis. The protein-protein interaction network and miRNA-mRNA regulatory network were performed by Search Tool for the Retrieval of Interacting Genes database and Cytoscape software. RESULTS: A total of 27 differentially expressed miRNAs (25 upregulated and 2 downregulated) and 561 DEGs (429 upregulated and 132 downregulated) were identified. Five miRNAs (miR-151b, miR-151a-5p, let-7a-2-3p, miR-363-3p, miR-20b-5p) had prognostic significance in AML. The gene ontology analysis showed that upregulated DEGs suggested significant enrichment in MHC class II protein complex, extracellular structure organization, blood vessel development, cell morphogenesis involved in differentiation, embryonic morphogenesis, regulation of cell adhesion, and so on. Similarly, the downregulated DEGs were mainly enriched in secretory granule lumen, extracellular structure organization. In the gene set enrichment analysis of Kyoto Encyclopedia of Genes and Genomes pathways, the RUNX1 mutation was associated with adherent junction, WNT signaling pathway, JAK-STAT signaling pathway, pathways in cancer, cell adhesion molecules CAMs, MAPK signaling pathway. Eleven genes (PPBP, APP, CCR5, HLA-DRB1, GNAI1, APLNR, P2RY14, C3AR1, HTR1F, CXCL12, GNG11) were simultaneously identified by hub gene analysis and module analysis. MicroRNA-363-3p may promote the development of RUNX1 mutation AML, targeting SPRYD4 and FNDC3B. In addition, the RUNX1 mutation rates in patient were obviously correlated with age, white blood cell, FAB type, risk(cyto), and risk(molecular) (P < .05). CONCLUSION: Our findings have indicated that multiple genes and microRNAs may play a crucial role in RUNX1 mutation AML. MicroRNA-363-3p may promote the development of RUNX1 mutation AML by targeting SPRYD4 and FNDC3B.

Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation.

BACKGROUND: DNA methyltransferase 3 alpha (DNMT3A) mutation was one of the most frequent genetic alterations in acute myeloid leukemia (AML), which was associated with poor prognosis and appeared to be a potential biomarker. Herein, we aimed to identify the key genes and pathways involved in adult AML with DNMT3A mutations and to find possible therapeutic targets for improving treatment. METHODS: The RNA sequencing datasets of 170 adult AML patients were obtained from The Cancer Genome Atlas (TCGA) database. EdgeR of the R platform was used to identify the differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape and DAVID. And protein-protein interaction (PPI) network and clustering modules were analyzed with the STRING database and Cytoscape software. RESULTS: Mutated DNMT3A resulted in a shorter overall survival (OS) in AML patients and obviously associated with age, blast percentage in peripheral blood, and FLT3 mutation. A total of 283 DEGs were detected, of which 95 were upregulated and 188 were downregulated. GO term analysis showed that DEGs were significantly enriched in neutrophil degranulation, myeloid cell differentiation, stem cell proliferation, positive regulation of neurological system process, leukocyte migration, and tissue morphogenesis. KEGG pathway enrichment analysis indicated that the pathway of cancer, PI3K-Akt signaling pathway, and transcriptional misregulation in cancer may play a crucial role in DNMT3A mutation AML. Seven hub genes (BMP4, MPO, THBS1, APP, ELANE, HOXA7, and VWF) had a significant prognostic value. CONCLUSION: Bioinformatics analysis in the present study provided novel targets for early diagnosis and new strategies for treatment for AML with DNMT3A mutation.

Identification of the key genes and microRNAs in adult acute myeloid leukemia with FLT3 mutation by bioinformatics analysis.

Background: Associated with poor prognosis, FMS-like tyrosine kinase 3 (FLT3) mutation appeared frequently in acute myeloid leukemia (AML). Herein, we aimed to identify the key genes and miRNAs involved in adult AML with FLT3 mutation and find possible therapeutic targets for improving treatment. Materials: Gene and miRNA expression data and survival profiles were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. EdgeR of R platform was applied to identify the differentially expressed genes and miRNAs (DEGs, DE-miRNAs). Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape and DAVID. And protein-protein interaction network, miRNA-mRNA regulatory network and clustering modules analyses were performed by STRING database and Cytoscape software. Results: Survival analysis showed FLT3 mutation led to adverse outcome in AML. 24 DE-miRNAs (6 upregulated, 18 downregulated) and 250 DEGs (54 upregulated, 196 downregulated) were identified. Five miRNAs had prognostic value and the results matched their expression levels (miR-1-3p, miR-10a-3p, miR-10a-5p, miR-133a-3p and miR-99b-5p). GO analysis showed DEGs were enriched in skeletal system development, blood vessel development, cartilage development, tissue morphogenesis, cartilage morphogenesis, cell morphogenesis involved in differentiation, response to growth factor, cell-substrate adhesion and so on. The KEGG analysis showed DEGs were enriched in PI3K-Akt signaling pathway, ECM-receptor interaction and focal adhesion. Seven genes (LAMC1, COL3A1, APOB, COL1A2, APP, SPP1 and FSTL1) were simultaneously identified by hub gene analysis and module analysis. SLC14A1, ARHGAP5 and PIK3CA, the target genes of miR-10a-3p, resulted in poor prognosis. Conclusion: Our study successfully identified molecular markers, processes and pathways affected by FLT3 mutation in AML. Furthermore, miR-10a-3p, a novel oncogene, might involve in the development of FLT3 mutation adult AML by targeting SLC14A1, ARHGAP5 and PIK3CA.

Status and prognostic nomogram of patients with Burkitt lymphoma.

The purpose of the present study was to evaluate the newest status of patients diagnosed Burkitt lymphoma (BL), an aggressive lymphoma subset with a high cure rate. Furthermore, the study aimed to create prognostic nomograms to consider various prognostic factors and estimate patient survival, paving the way for clinical decision-making. A total of 4,600 patients diagnosed with BL between 1983 and 2015 were investigated, via data collected from the SEER database. The overall status of the patients was analyzed through several aspects, including incidence and survival analysis of the previous three decades using the log-rank test and the Kaplan-Meier method. In order to construct and validate the nomograms, the patient diagnosed during 2005-2015 were randomly assigned to the training cohort and validation cohort. Univariate and multivariate analyses were applied to identify independent factors that were further included in the nomograms, predicting 3- and 5-year overall survival (OS) and cancer-specific survival (CSS). The data of the training cohort were used for internal validation and validation cohort used to external validation. C-index and calibration plots were used to validate the nomograms, comparing predicted values with actual outcomes. The incidence of BL was gradually increased from 1984 and reached its peak in 2009, at a rate of 0.491 per 100,000 [95% confidence interval (CI), 0.412-0.581]. From 2009, the incidence slowly declined year by year and dropped to 0.280 per 100,000 (95% CI, 0.224-0.346). The OS and CSS rates of patients diagnosed between 2005 and 2015 were increased, in contrast with those of patients diagnosed from 1983-1993 and 1994-2004. A total of five variables, including age, race, chemotherapy, primary site and stage, proved to be the prognostic factors of BL and were used to construct the nomograms predicting 3- and 5-year OS and CSS. The internal and external calibration plots for the probability of 3- and 5-year OS and CSS were consistent between nomogram prediction and observed outcomes. The slow decline in incidence and the significantly improved cure rate make BL a disease that is no longer an urgent problem. Effective nomograms were developed to predict the OS and CSS of patients with BL.