Identification and validation of hub genes and molecular classifications associated with chronic myeloid leukemia
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PROVIDER: S-EPMC10811081 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundChronic myeloid leukemia (CML) is a malignant hyperplastic tumor of the bone marrow originating from pluripotent hematopoietic stem cells. The advent of tyrosine kinase inhibitors (TKIs) has greatly improved the survival rate of patients with CML. However, TKI-resistance leads to the disease recurrence and progression. This study aimed to identify immune-related genes (IRGs) associated with CML progression.MethodsWe extracted the gene's expression profiles from the Gene Expression Omnibus (GEO). Bioinformatics analysis was used to determine the differentially expressed IRGs of CML and normal peripheral blood mononuclear cells (PBMCs). Functional enrichment and gene set enrichment analysis (GSEA) were used to explore its potential mechanism. Hub genes were identified using Molecular Complex Detection (MCODE) and the CytoHubba plugin. The hub genes' diagnostic value was evaluated using the receiver operating characteristic (ROC). The relative proportions of infiltrating immune cells in each CML sample were evaluated using CIBERSORT. Quantitative real-time PCR (RT-qPCR) was used to validate the hub gene expression in clinical samples.ResultsA total of 31 differentially expressed IRGs were identified. GO analyses revealed that the modules were typically enriched in the receptor ligand activity, cytokine activity, and endopeptidase activity. KEGG enrichment analysis of IRGs revealed that CML involved Th17 cell differentiation, the NF-kappa B signaling pathway, and cytokine-cytokine receptor interaction. A total of 10 hub genes were selected using the PPI network. GSEA showed that these hub genes were related to the gamma-interferon immune response, inflammatory response, and allograft rejection. ROC curve analysis suggested that six hub genes may be potential biomarkers for CML diagnosis. Further analysis indicated that immune cells were associated with the pathogenesis of CML. The RT-qPCR results showed that proteinase 3 (PRTN3), cathepsin G (CTSG), matrix metalloproteinase 9 (MMP9), resistin (RETN), eosinophil derived neurotoxin (RNase2), eosinophil cationic protein (ECP, RNase3) were significantly elevated in CML patients' PBMCs compared with healthy controls.ConclusionThese results improved our understanding of the functional characteristics and immune-related molecular mechanisms involved in CML progression and provided potential diagnostic biomarkers and therapeutic targets.
| S-EPMC8781323 | biostudies-literature
Project description:Chemotherapy resistance is a major obstacle in cancer therapy, and identifying novel druggable targets to reverse this phenomenon is essential. The exosome-mediated transmittance of drug resistance has been shown in various cancer models including ovarian and prostate cancer models. In this study, we aimed to investigate the role of exosomal miRNA transfer in chronic myeloid leukemia drug resistance. For this purpose, firstly exosomes were isolated from imatinib sensitive (K562S) and resistant (K562R) chronic myeloid leukemia (CML) cells and named as Sexo and Rexo, respectively. Then, miRNA microarray was used to compare miRNA profiles of K562S, K562R, Sexo, Rexo, and Rexo-treated K562S cells. According to our results, miR-125b-5p and miR-99a-5p exhibited increased expression in resistant cells, their exosomes, and Rexo-treated sensitive cells compared to their sensitive counterparts. On the other hand, miR-210-3p and miR-193b-3p were determined to be the two miRNAs which exhibited decreased expression profile in resistant cells and their exosomes compared to their sensitive counterparts. Gene targets, signaling pathways, and enrichment analysis were performed for these miRNAs by TargetScan, KEGG, and DAVID. Potential interactions between gene candidates at the protein level were analyzed via STRING and Cytoscape software. Our findings revealed CCR5, GRK2, EDN1, ARRB1, P2RY2, LAMC2, PAK3, PAK4, and GIT2 as novel gene targets that may play roles in exosomal imatinib resistance transfer as well as mTOR, STAT3, MCL1, LAMC1, and KRAS which are already linked to imatinib resistance. MDR1 mRNA exhibited higher expression in Rexo compared to Sexo as well as in K562S cells treated with Rexo compared to K562S cells which may suggest exosomal transfer of MDR1 mRNA.
| S-EPMC11582232 | biostudies-literature
Project description:Purpose: Chronic myeloid leukemia stem cells (CML-LSCs) are posited as the primary instigators of resistance to tyrosine kinase inhibitors (TKIs) and recurrence of CML. Ubiquitination, a post-translational modification, has been implicated in the worsening process of CML. A more detailed understanding of their crosstalk needs further investigation. Our research aims to explore the potential ubiquitination-related genes in CML-LSC using bioinformatics analysis that might be the target for the eradication of LSCs. Methods: The ubiquitination modification-related differentially expressed genes (UUC-DEGs) between normal hematopoietic stem cells (HSCs) and LSCs were obtained from GSE47927 and iUUCD database. Subsequently, the hub UUC-DEGs were identified through protein-protein interaction (PPI) network analysis utilizing the STRING database and the MCODE plug-in within the Cytoscape platform. The upstream regulation network of the hub UUC-DEGs was studied by hTFtarget, PROMO, miRDB and miRWalk databases respectively. Then the correlation between the hub UUC-DEGs and the immune cells was analyzed by the CIBERSORT algorithm and "ggcorrplot" package. Finally, we validated the function of hub UUC-DEGs in CML animal models, CML cell lines and CD34+ cells of the GSE24739 dataset. Results: There is a strong association between the 4 hub UUC genes (AURKA, Fancd2, Cdc20 and Uhrf1) of LSCs and the infiltration of CD4+/CD8+ T cells, NK cells and monocytes. 8 TFs and 23 miRNAs potentially targeted these 4 hub genes were constructed. Among these hub genes, Fancd2, Cdc20 and Uhrf1 were found to be highly expressed in CML-LSC, which knocking down resulted in significant inhibition of CML cell proliferation. Conclusions: From the perspective of bioinformatics analysis, UHRF1 and CDC20 were identified as the novel key ubiquitination-related genes in CML-LSCs and the pathogenesis of CML.
| S-EPMC11190763 | biostudies-literature
Project description:BackgroundThis study aims to identify the hub genes and immune-related pathways in acute myeloid leukemia (AML) to provide new theories for immunotherapy.MethodsWe use bioinformatics methods to find and verify the hub gene. At the same time, we use the results of GSEA enrichment analysis to find immune-related mediators. Through Mendelian randomization(MR) analysis, on the one hand, we look for related immune cells, and on the other hand, we use it to determine the causal relationship among immune cells, immune mediators, and AML. Finally, in vitro experiments are conducted to further verify and improve the reliability and physiological functions of the hub gene and its immune-related pathways.ResultsComplement Factor D(CFD) gene is identified as the highly expressed hub gene and is positively correlated with IL-2. IL-2 is also positively correlated with CD27 on CD24+CD27+B cells, JAK/STAT, and PI3K/Akt. The latter three are positively correlated with the occurrence and development of AML.ConclusionWe conclude that CFD gene uses IL-2 as a mediator to promote the disease progression of AML by promoting the CD27 on CD24+CD27+B cells, JAK-STAT, and PI3K-Akt pathways.
| S-EPMC11757261 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a malignancy of hematopoietic stem cells. Although many candidate genes such as CEBPA, FLT3, IDH1, and IDH2 have been associated with AML initiation and prognosis, the molecular mechanisms underlying this disease remain unclear. In this study, we used a systemic co-expression analysis method, namely weighted gene co-expression network analysis (WGCNA), to identify new candidate genes associated with adult AML progression and prognosis. We identified around 5,138 differentially expressed genes (DEGs) between AML samples (from The Cancer Genome Atlas database) and normal control samples (from the Genotype-Tissue Expression database). WGCNA identified nine co-expression modules with significant differences based on the DEGs. Among modules, the turquoise and blue ones were the most relevant to AML (P-value: turquoise 0, blue 4.64E-77). GO term and KEGG pathway analyses revealed that pathways that are commonly dysregulated in AML were all enriched in the blue and turquoise modules. A total of 15 hub genes were identified to be crucial for AML progression. PIVOT analysis revealed non-coding RNAs, transcriptional factors, and drugs associated with the hub genes. Finally, survival analysis revealed that one of the hub genes, CEACAM5, was significantly associated with AML prognosis and could serve as a potential target for AML treatment.
| S-EPMC7950274 | biostudies-literature
Project description:BackgroundWe identified the hub genes and pathways dysregulated in acute myeloid leukemia and the potential molecular mechanisms involved.MethodsWe downloaded the GSE15061 gene expression dataset from the Gene Expression Omnibus database and used weighted gene co-expression network analysis to identify hub genes. Differential expression of the genes was evaluated using the limma package in R software. Subsequently, we built a protein-protein interaction network followed by functional enrichment analysis. Then, the prognostic significance of gene expression was explored in terms of overall survival. Finally, transcription factor-mRNA (ribonucleic acid) and microRNA-mRNA interaction analysis was also explored.ResultsWe identified 100 differentially expressed hub genes. Functional enrichment analysis indicated that the genes were principally involved in immune system regulation, host defense, and negative regulation of apoptosis and myeloid cell differentiation. We identified 4 hub genes, the expression of which was significantly correlated with overall survival. Finally, 26 key regulators for hub genes and 38 microRNA-mRNA interactions were identified.ConclusionWe performed a comprehensive bioinformatics analysis of hub genes potentially involved in acute myeloid leukemia development. Further molecular biological experiments are required to confirm the roles played by these genes.
| S-EPMC7458232 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a group of heterogeneous hematological malignancies. We identified key genes as ITGAM and lncRNA ITGB2-AS1 through different bioinformatics tools. Furthermore, qPCR was performed to verify the expression level of essential genes in clinical samples. Retrospective research on 179 AML cases was used to investigate the relationship between the expression of ITGAM and the characteristics of AML. The critical gene relationship with immune infiltration in AML was estimated. The clinical validation and prognostic investigation showed that ITGAM, PPBP, and ITGB2-AS1 are highly expressed in AML (P < 0.001) and significantly associated with the overall survival in AML. Moreover, the retrospective research on 179 clinical cases showed that positive expression of ITGAM is substantially related to AML classification (P < 0.001), higher count of white blood cells (P < 0.01), and poor chemotherapy outcome (P < 0.05). Furthermore, based on grouping ITGAM as the high and low expression in TCGA-LAML profile, we found that genes in the highly expressed ITGAM group are mainly involved in immune infiltration and inflammation-related signaling pathways. Finally, we discovered that the expression level of ITGAM and lncRNA ITGB2-AS1 are not just closely related to the immune score and stromal score (P < 0.001) but also significantly positively correlated with various Immune signatures in AML (P < 0.001), indicating the association of these genes with immunosuppression in AML. The prediction of candidate drugs indicated that certain immunosuppressive drugs have potential therapeutic effects for AML. The critical genes could be used as potential biomarkers to evaluate the survival and prognosis of AML.
| S-EPMC8266366 | biostudies-literature
Project description:Detailed information on the crystal structure of the pharmacologically targeted domains of the BCR-ABL molecule and on its intracellular signaling, which are potentially involved in growth, anti-apoptosis, metabolism and stemness, has made the study of chronic myeloid leukemia the most successful field in tumor biology. However, we now face the issue of drug resistance due to deregulation in the quality control of both DNA and protein. BCR-ABL is basically a misfolded protein with intrinsically disordered regions, which not only produces endoplasmic reticulum stress followed by unfolded protein response in some settings, but also conformational plasticity that may affect the structure of the whole molecule. The intercellular signaling derived from the leukemic cell microenvironment may influence the intracellular responses that take place in a manner both dependent on and independent of BCR-ABL tyrosine kinase activity.
| S-EPMC7659193 | biostudies-literature
Project description:AimImatinib is a tyrosine kinase inhibitor that has revolutionized the treatment of chronic myeloid leukemia (CML). Despite its efficacy, about a third of patients discontinue the treatment due to therapy failure or intolerance. The rational identification of patients less likely to respond to imatinib would be of paramount clinical relevance. We have shown that transmembrane transporter hOCT1 genotyping predicts imatinib activity. In parallel, Polycomb group genes (PcGs) are epigenetic repressors implicated in CML progression and in therapy resistance.Patients & methodsWe measured the expression of eight PcGs in paired pre- and post-imatinib bone marrow samples from 30 CML patients.ResultsBMI1, PHC3, CBX6 and CBX7 expression was significantly increased during imatinib treatment. Post-treatment levels of CBX6 and CBX7 predicted 3-month response rate. Measurement of post-treatment BMI1 levels improved the predictive power of hOCT1 genotyping.ConclusionThese results suggest that the expression levels of PcGs might be useful for a more accurate risk stratification of CML patients.
| S-EPMC5551942 | biostudies-literature
Project description:Neutrophil infiltration plays a key role in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). However, pertinent mechanisms remain poorly elucidated. Here, we obtained the data from gene expression omnibus (GEO) and gene set enrichment analysis (GSEA) to identify and validate neutrophil-associated hub genes in CRSwNP. We found that four neutrophil-associated hub genes, namely ICAM1, IL-1β, TYROBP, and BCL2A1, were markedly upregulated and positively correlated with neutrophil infiltration levels in patients with CRSwNP. Subsequently, this was confirmed by real-time quantitative PCR. In conclusion, we identified the role of neutrophil infiltration in the pathophysiology of CRSwNP, which may be the potential targets for the diagnosis and treatment of CRSwNP.
| S-EPMC11350000 | biostudies-literature