MicroRNA biomarker identification for pediatric acute myeloid leukemia based on a novel bioinformatics model.
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ABSTRACT:
SUBMITTER: Yan W
PROVIDER: S-EPMC4694912 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples-1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples-127 primary and 37 relapse samples-were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ? .001) or low risk (hazard ratio, 0.323; P ? .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.
| S-EPMC5721230 | biostudies-literature
Project description:The most important reason for therapy failure in pediatric acute myeloid leukemia (AML) is relapse. In order to identify miRNAs that contribute to the clonal evolution towards relapse in pediatric AML, miRNA expression profiling of 127 de novo pediatric AML cases were used. In the diagnostic phase, no miRNA signatures could be identified that were predictive for relapse occurrence, in a large pediatric cohort, nor in a nested mixed lineage leukemia (MLL)-rearranged pediatric cohort. AML with MLL- rearrangements are found in 15-20% of all pediatric AML samples, and reveal a relapse rate up to 50% for certain translocation partner subgroups. Therefore, microRNA expression profiling of six paired initial diagnosis-relapse MLL-rearranged pediatric AML samples (test cohort) and additional eight paired initial diagnosis-relapse samples with MLL-rearrangements (validation cohort) was performed. A list of 53 differentially expressed miRNAs was identified of which the miR-106b~25 cluster, located in intron 13 of MCM7, was the most prominent. These differentially expressed miRNAs however could not predict a relapse in de novo AML samples with MLL-rearrangements at diagnosis. Furthermore, higher mRNA expression of both MCM7 and its upstream regulator E2F1 was found in relapse samples with MLL-rearrangements. In conclusion, we identified the miR-106b~25 cluster to be upregulated in relapse pediatric AML with MLL-rearrangements.
| S-EPMC5217027 | biostudies-literature
Project description:BACKGROUND RUNXl plays a key regulatory role in the process of hematopoiesis and is a common target for multiple chromosomal translocations in human acute leukemia. Mutations of RUNX1 gene can lead to acute leukemia and affect the prognosis of AML patients. We aimed to identify pivotal genes and pathways involved in RUNX1-mutated patients of with acute myeloid leukemia (AML) and to explore possible molecular markers for novel therapeutic targets of the disease. MATERIAL AND METHODS The RNA sequencing datasets of 151 cases of AML were obtained from the Cancer Genome Atlas database. Differentially expressed genes (DEGs) were identified using edgeR of the R platform. PPI (protein-protein interaction) network clustering modules were analyzed with ClusterONE, and the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analyses for modules were performed. RESULTS A total of 379 genes were identified as DEGs. The KEGG enrichment analysis of DEGs showed significantly enriched pathways in cancer, extracellular matrix (ECM)-receptor interaction pathway, and cyclic adenosine monophosphate (cAMP) signaling pathway. The top 10 genes ranked by degree were PRKACG, ANKRD7, RNFL7, ROPN11, TEX14, PRMT8, OTOA, CFAP99, NRXN1, and DMRT1, which were identified as hub genes from the protein-protein interaction network (PPI). Statistical analysis revealed that RUNX1-mutated patients with AML had a shorter median survival time (MST) with poor clinical outcome and an increased risk of death when compared with those without RUNX1 mutations. CONCLUSIONS DEGs and pathways identified in the present study will help understand the molecular mechanisms underlying RUNX1 mutations in AML and develop effective therapeutic strategies for RUNX1-mutation AML.
| S-EPMC6186152 | biostudies-other
Project description:The aim of the present study was to examine the expression and clinical significance of long non-coding RNA (lncRNA)-CCDC26 in patients with acute myeloid leukemia (AML), and to investigate the potential functions of CCDC26. The Gene Expression Omnibus database and reverse transcription-quantitative polymerase chain reaction analysis were used to detect the expression levels of CCDC26 in patients with AML and healthy volunteers. Clinical data for 93 patients with AML were collected to analyze the clinical significance of CCDC26. Weighted gene co-expression network analysis (WGCNA), a protein-protein interaction (PPI) network, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were used to examine the functions of CCDC26. The expression levels of CCDC26 in the initially diagnosed and relapsed patients with AML were significantly upregulated compared with the control group. The upregulated expression level of CCDC26 in patients with AML was significantly associated with age, anemia, risk stratification and remission. Furthermore, patients with a high CCDC26 expression level had a poorer overall survival (P=0.0105). In addition, the area under the curve (AUC)1year and AUC2year of CCDC26 for overall survival were 0.722 and 0.686, respectively. WGCNA, PPI network and KEGG pathway analysis revealed that CCDC26 was involved in the regulation of a number of biological processes. lncRNA-CCDC26 may serve as a novel biomarker for monitoring the progression and predicting the clinical outcome of AML.
| S-EPMC6676650 | biostudies-literature
Project description:Background: Acute Myeloid Leukemia (AML) is a complex and heterogeneous hematologic malignancy. However, the function of prognosis-related signature genes in AML remains unclear. Methods: In the current study, transcriptome sequencing was performed on 15 clinical samples, differentially expressed RNAs were identified using R software. The potential interactions network was constructed by using the common genes between target genes of differentially expressed miRNAs with transcriptome sequencing results. Functional and pathway enrichment analysis was performed to identify candidate gene-mediated aberrant signaling pathways. Hub genes were identified by the cytohubba plugin in Cytoscape software, which then expanded the potential interactions regulatory module for hub genes. TCGA-LAML clinical data were used for the prognostic analysis of the hub genes in the regulatory network, and GVSA analysis was used to identify the immune signature of prognosis-related hub genes. qRT-PCR was used to verify the expression of hub genes in independent clinical samples. Results: We obtained 1,610 differentially expressed lncRNAs, 233 differentially expressed miRNAs, and 2,217 differentially expressed mRNAs from transcriptome sequencing. The potential interactions network is constructed by 12 lncRNAs, 25 miRNAs, and 692 mRNAs. Subsequently, a sub-network including 15 miRNAs as well as 12 lncRNAs was created based on the expanded regulatory modules of 25 key genes. The prognostic analysis results show that CCL5 and lncRNA UCA1 was a significant impact on the prognosis of AML. Besides, we found three potential interactions networks such as lncRNA UCA1/hsa-miR-16-5p/COL4A5, lncRNA UCA1/hsa-miR-16-5p/SPARC, and lncRNA SNORA27/hsa-miR-17-5p/CCL5 may play an important role in AML. Furthermore, the evaluation of the immune infiltration shows that CCL5 is positively correlated with various immune signatures, and lncRNA UCA1 is negatively correlated with the immune signatures. Finally, the result of qRT-PCR showed that CCL5 is down-regulated and lncRNA UCA1 is up-regulated in AML samples separately. Conclusions: In conclusion, we propose that CCL5 and lncRNA UCA1 could be recognized biomarkers for predicting survival prognosis based on constructing competing endogenous RNAs in AML, which will provide us novel insight into developing novel prognostic, diagnostic, and therapeutic for AML.
| S-EPMC8585857 | biostudies-literature
Project description:Acute myeloid leukemia is a heterogeneous disease that accounts for approximately 20% of acute leukemias in children and adolescents. Despite the lack of targeted therapy for most subtypes and a dearth of new agents, survival rates have reached approximately 60% for children treated on clinical trials in developed countries. Most of the advances have been accomplished by better risk classification, the implementation of excellent supportive care measures, adaptation of therapy on the basis of each patient's response to therapy, and improvements in allogeneic hematopoietic stem cell transplantation. However, it is unlikely that further gains can be made through these measures alone. In this regard, high-resolution, genome-wide analyses have led to greater understanding of the pathogenesis of this disease and the identification of molecular abnormalities that are potential targets of new therapies. The development of molecularly targeted agents, some of which are already in clinical trials, holds great promise for the future.
| S-EPMC3383013 | biostudies-literature
Project description:Nucleophosmin (NPM1) is a widely expressed nucleocytoplasmic shuttling protein with prominent nucleolar localization. It is estimated that 25-35% of adult patients with acute myeloid leukemia (AML) carry NPM1 mutations. The classic NPM1 type A mutation occurs in exon 12, which accounts for 75-80% of adult patients with NPM1-mutated AML. It produces an additional leucine and valine-rich nuclear export signal (NES) at the C-terminus, and causes aberrant cytoplasmic dislocation of NPM1 protein. Notably, emerging evidence indicates that besides the classic type A mutation, rare mutants occurring in other exons may also lead to the imbalance of the nucleocytoplasmic shuttle of NPM1. Identification of novel non-type A mutants is crucial for the diagnosis, prognosis, risk stratification and disease monitoring of potential target populations. Here we reported a novel NPM1 mutation in exon 5 identified from a de novo AML patient. Similar to the classic type A mutation, the exon 5 mutation had the NPM1 mutant bound to exportin-1 and directed the mutant into the cytoplasm by generating an additional NES sequence, resulting in aberrant cytoplasmic dislocation of NPM1 protein, which could be reversed by exportin-1 inhibitor leptomycin B. Our findings strongly support that besides the exon 12 mutation, the exon 5 mutant is another NPM1 "born to be exported" mutant critical for leukemogenesis. Therefore, similar to the classic type A mutation, the identification of our novel NPM1 mutation is beneficial for clinical laboratory diagnosis, genetic risk assessment and MRD monitoring.
| S-EPMC10548603 | biostudies-literature
Project description:Acute myelogenous leukemia (AML) is a common malignancy and is supposed to have the ability to escape host immune surveillance. The present study aimed to identify key genes in AML that may affect tumor immunity and to provide prognosis biomarkers of AML. The Cancer Genome Atlas (TCGA) dataset was screened for transcription factors (TFs) involved in immunity and influencing survival, combining Gene Expression Omnibus (GEO) data to validate the impact on patient survival. A prognostic signature was established using four transcription factors, and these genes play an important role in the immune system, with higher regulatory T cell (Treg) scores in high-risk patients compared with the low-risk group. Analysis of individual genes showed that STAT4 and Treg are closely related, which may be due to STAT4 transcribing related genes that affect immunity. STAT4 expression was positively correlated with the proportion of abnormal cells and promoted AML recurrence as verified by AML clinical patient samples. In addition, silencing of STAT4 significantly slowed down the proliferation capacity of HL60 cells. In conclusion, these findings suggest that STAT4 may be a potential biomarker for AML prognosis. As a key gene affecting the prognosis of AML patients, STAT4 has the potential to be a candidate diagnostic and prognostic biomarker for AML.
| S-EPMC10861362 | biostudies-literature
Project description:Accumulating evidence has indicated that microRNA-181 (miR-181) is dysregulated in hematological malignancies, and associates with the clinical outcomes. However, the association of miR-181 expression levels with acute myeloid leukemia (AML) remains inconclusive, as publications from different groups have reported contradictory results. In this manuscript, a meta-analysis was performed to assess the prognostic significance of miR-181 in AML patients. Eligible studies were retrieved from PubMed, Embase and Cochrane Library databases, and a total of 6 studies including 815 AML patients were included in the final analysis. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were extracted and pooled to investigate the correlation between miR-181 and the survival of AML patients. Our results showed that elevated miR-181 expression was associated with increased survival in 395 American patients, and reduced survival in 325 Chinese patients. Both subgroup analyses and meta-regression indicated that the origin of AML patients contributed to the heterogeneity in the datasets evaluating the correlation between overall survival (OS) and miR-181. These results indicate that miR-181 can be used as a promising prognostic biomarker in AML patients, which may depend on the origin of patient population.
| S-EPMC5687675 | biostudies-literature
Project description:BackgroundAcute myeloid leukemia (AML) is a clonal malignant disease with poor prognosis and a low overall survival rate. Although many studies on the treatment and detection of AML have been conducted, the molecular mechanism of AML development and progression has not been fully elucidated. The present study was designed to pursuit the molecular mechanism of AML using a comprehensive bioinformatics analysis, and build an applicable model to predict the survival probability of AML patients in clinical use.MethodsTo simplify the complicated regulatory networks, we performed the gene co-expression and PPI network based on WGCNA and STRING database using modularization design. Two machine learning methods, A least absolute shrinkage and selector operation (LASSO) algorithm and support vector machine-recursive feature elimination (SVM-RFE), were used to filter the common hub genes by five-fold cross-validation. The candidate hub genes were used to build the predictive model of AML by the cox-proportional hazards analysis, and validated in The Cancer Genome Atlas (TCGA) cohort and ohsu cohort, which were reliable in the experimental verification by qRT-PCR and western blotting in mRNA and protein levels.ResultsThree hub genes, FLT3, CD177 and TTPAL were used to build a clinically applicable model to predict the survival probability of AML patients and divided them into high and low groups. To compare the survival ability of the model with the classical clinical features, we generated the nomogram. The model displayed the most risk points contrast to other clinical characteristics, which was compatible with the data of cox multivariate regression.ConclusionThis study reveal the novel molecular mechanism of AML, and construct a clinical model significantly related to AML patient prognosis. We showed the integrated roles of critical pathways, hub genes associated, which provide potential targets and new research ideas for the treatment and early detection of AML.
| S-EPMC7655922 | biostudies-literature