Frequent variations in cancer-related genes may play prognostic role in treatment of patients with chronic myeloid leukemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Lavrov AV
PROVIDER: S-EPMC4895599 | biostudies-literature | 2016 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundChemotactic cytokines play a crucial role in the development of acute myeloid leukemia (AML). Thus, investigating the mechanisms of chemotactic cytokine-related genes (CCRGs) in AML is of paramount importance.MethodsUsing the TCGA-AML, GSE114868, and GSE12417 datasets, differential expression analysis identified differentially expressed CCRGs (DE-CCRGs). These genes were screened by overlapping differentially expressed genes (DEGs) between AML and control groups with CCRGs. Subsequently, functional enrichment analysis and the construction of a protein-protein interaction (PPI) network were conducted to explore the functions of the DE-CCRGs. Univariate Cox regression, least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analyses identified relevant prognostic genes and developed a prognostic model. Survival analysis of the prognostic gene was performed, followed by functional similarity analysis, immune analysis, enrichment analysis, and drug prediction analysis.ResultsDifferential expression analysis revealed 6,743 DEGs, of which 29 DE-CCRGs were selected for this study. Functional enrichment analysis indicated that DE-CCRGs were primarily involved in chemotactic cytokine-related functions and pathways. Six prognostic genes (CXCR3, CXCR2, CXCR6, CCL20, CCL4, and CCR2) were identified and incorporated into the risk model. The model's performance was validated using the GSE12417 dataset. Survival analysis showed significant differences in AML overall survival (OS) between prognostic gene high and low expression groups, indicating that prognostic gene might be significantly associated with patient survival. Additionally, nine different immune cells were identified between the two risk groups. Correlation analysis revealed that CCR2 had the most significant positive correlation with monocytes and the most significant negative correlation with resting mast cells. The tumor immune dysfunction and exclusion score was lower in the high-risk group.ConclusionCXCR3, CXCR2, CXCR6, CCL20, CCL4, and CCR2 were identified as prognostic genes correlated to AML and the tumor immune microenvironment. These findings offerred novel insights into the prevention and treatment of AML.
| S-EPMC11318587 | biostudies-literature
Project description:BackgroundOne of the most prevalent hematological system cancers is acute myeloid leukemia (AML). Efferocytosis-related genes (ERGs) and N6-methyladenosine (m6A) have an important significance in the progression of cancer, and the metastasis of tumors.MethodsThe AML-related data were collected from The Cancer Genome Atlas (TCGA; TCGA-AML) database and Gene Expression Omnibus (GEO; GSE9476, GSE71014, and GSE13159) database. The "limma" R package and Venn diagram were adopted to identify differentially expressed ERGs (DE-ERGs). The m6A related-DE-ERGs were obtained by Spearman analysis. Subsequently, univariate Cox and Least Absolute Shrinkage and Selection Operator (LASSO) were used to construct an m6A related-ERGs risk signature for AML patients. The possibility of immunotherapy for AML was explored. The pRRophetic package was adopted to calculate the IC50 of drugs for the treatment of AML. Finally, the expression of characterized genes was validated by quantitative reverse transcription-PCR (qRT-PCR).ResultsBased on m6A related-DE-ERGs, a prognostic model with four characteristic genes (UCP2, DOCK1, SLC14A1, and SLC25A1) was constructed. The risk score of model was significantly associated with the immune microenvironment of AML, with four immune cell types, 14 immune checkpoints, 20 HLA family genes and, immunophenoscore (IPS) all showing differences between the high- and low-risk groups. A total of 56 drugs were predicted to differ between the two groups, of which Erlotinib, Dasatinib, BI.2536, and bortezomib have been reported to be associated with AML treatment. The qRT-PCR results showed that the expression trends of DOCK1, SLC14A1 and SLC25A1 were consistent with the bioinformatics analysis.ConclusionIn summary, 4 m6A related- ERGs were identified and the corresponding prognostic model was constructed for AML patients. This prognostic model effectively stratified the risk of AML patients.
| S-EPMC10704160 | biostudies-literature
Project description:A previous study has demonstrated a significant decrease in the TCR? gene expression level in chronic myeloid leukemia (CML); thus, we further investigated the expression of TCR?-regulating factors, the distribution of the TCR? 3' untranslated region (3'-UTR) splice variants, and the expression level and correlation of the alternative splicing factor/splicing factor 2 (ASF/SF-2), Fc?RI? and ZAP-70 genes. TCR? 3'-UTR splice variants were identified in peripheral blood mononuclear cells (PBMCs) from 14 healthy individuals, 40 patients with CML and 22 patients with CML in complete remission (CML-CR) by RT-PCR. The expression level of the TCR?, Fc?RI?, ASF/SF-2 and ZAP-70 genes was analyzed by real-time quantitative PCR. While the expression of TCR? gene in the CML group was significantly lower than that in the healthy individual and CML-CR groups, a significantly higher expression of the FceRI? and ASF/SF-2 genes was found in the CML group. Two types of splicing forms were detected in all of the healthy individual CML-CR cases: wild type (WT) TCR? 3'-UTR and alternatively splieced (AS) TCR? 3'-UTR which have been alternatively splieced in the WT TCR? 3'-UTR . However, 35% of the CML cases contained only the wild type TCR? 3'-UTR isoform. Based on the TCR? 3'-UTR isoform expression characteristic, we divided the patients with CML into two subgroups: the WT+AS- CML group, containing patients that express only the wild type TCR? 3'-UTR, and the WT+AS+ CML group, which contained patients that expressed two TCR? 3'-UTR isoforms. A significantly different ASF/SF-2 and Fc?RI? gene expression pattern was found between the WT+AS- and WT+AS+CML groups. We concluded that defective TCR? expression may be characterized in the WT+AS-and WT+AS+CML subgroups by the different gene expression pattern. The overexpression of ASF/SF2, which alternatively splices the TCR? 3'-UTR, is thought to participate in feedback regulation. The characteristics of TCR? 3'-UTR alternative splicing may be a novel immunological marker for the evaluation of the CML immune status.
| S-EPMC3544630 | biostudies-literature
Project description:Although tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML), the ability of TKIs to eradicate CML remains uncertain and patients must continue TKI therapy for indefinite periods. In this study, we performed whole-exome sequencing to identify somatic mutations in 24 patients with newly diagnosed chronic phase CML who were registered in the JALSG CML212 study. We identified 191 somatic mutations other than the BCR-ABL1 fusion gene (median 8, range 1-17). Age, hemoglobin concentration and white blood cell counts were correlated with the number of mutations. Patients with mutations ?6 showed higher rate of achieving major molecular response than those<6 (P=0.0381). Mutations in epigenetic regulator, ASXL1, TET2, TET3, KDM1A and MSH6 were found in 25% of patients. TET2 or TET3, AKT1 and RUNX1 were mutated in one patient each. ASXL1 was mutated within exon 12 in three cases. Mutated genes were significantly enriched with cell signaling and cell division pathways. Furthermore, DNA copy number analysis showed that 2 of 24 patients had uniparental disomy of chromosome 1p or 3q, which disappeared major molecular response was achieved. These mutations may play significant roles in CML pathogenesis in addition to the strong driver mutation BCR-ABL1.
| S-EPMC5436079 | biostudies-literature
Project description:Background: Acute myeloid leukemia (AML) is one of the most common cancers in the world, and oxidative stress is closely related to leukemia. A lot of effort has been made to improve the prognosis of AML. However, the situation remains serious. Hence, we focused on the study of prognostic genes in AML. Materials and Methods: Prognostic oxidative stress genes were screened out. The gene expression profile of AML patients was downloaded from the The Cancer Genome Atlas (TCGA) database. The oxidative stress-related model was constructed, by which the prognosis of AML patients was predicted using the two GEO GSE23143 datasets and the stability of the GSE71014 authentication model. Results: The prognostic oxidative stress genes were screened out in AML, and the prognostic genes were significantly enriched in a large number of pathways based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. There was a complex interaction between prognostic genes and transcription factors. After constructing the prediction model, the clinical predictive value of the model was discussed in a multi-omic study. We investigated the sensitivity of risk score to common chemotherapeutic agents, the influence of signaling pathways on the prognosis of AML patients, and the correlation of multiple genes with immune score and immune dysfunction. Conclusions: A highly effective prognostic risk model for AML patients was established and validated. The association of prognostic oxidative stress genes with drug sensitivity, signaling pathways, and immune infiltration was explored. The results suggested that oxidative stress genes promised to be potential prognostic biomarkers for AML, which may provide a new basis for disease management.
| S-EPMC8514868 | biostudies-literature
Project description:BackgroundAcute myeloid leukemia (AML), a common form of acute leukemia, is due to tumor changes and clonal proliferation caused by genetic variants. Cuproptosis is a novel form of regulated cell death. This study aimed to explore the role of cuproptosis-related genes (CRGs) in AML.MethodsInitially, differentially expressed genes (DEGs) between AML samples and normal samples were obtained by differential analysis, which were further intersected with the cuproptosis score-related genes (CSRGs) acquired by weighted gene co-expression network analysis (WGCNA) to obtain cuproptosis score-related differentially expressed genes (CS-DEGs). Then, a risk model was constructed by Cox analysis and least absolute shrinkage and selection operator (LASSO) analysis. Finally, immune infiltration analysis was performed and the functions and pathways of model genes were explored by single sample gene set enrichment analysis (ssGSEA).ResultsThirty-two CS-DEGs were obtained by overlapping 11,160 DEGs and 132 CSRGs. These 32 CS-DEGs were mainly enriched to cytoplasmic microtubule organization, RNA methylation, mTOR signaling pathway, and notch signaling pathway. Two model genes, PACS2 and NDUFV1, were finally screened for the construction of the risk model. In addition, PACS2 and NDUFV1 were significantly positively correlated with activated B cells, CD56dim natural killer (NK) cells, and negatively correlated with effector memory CD4 T cells and activated CD4 T cells. PACS2 gene was significantly enriched to inositol phosphate metabolism, histone modification, etc. NDUFV1 was mainly enriched to ncRNA metabolic process, 2-oxocarboxylic acid metabolism, and other pathways.ConclusionsA cuproptosis-related risk model consisting of PACS2 and NDUFV1 was built, which provided a new direction for the diagnosis and treatment of AML.
| S-EPMC10493802 | biostudies-literature
Project description:While the clinical impact of mutations in the ABL1 gene on response to therapy in chronic phase chronic myeloid leukemia (CP-CML) is well established, less is known about how other mutations affect prognosis. In a retrospective analysis, we identified 115 patients with CML (71 chronic, 15 accelerated and 29 blast phase) where targeted next-generation sequencing of genes recurrently mutated in myeloid leukemias was performed. ASXL1 was the most frequently mutated gene in the chronic (14%) and accelerated phase (40%) CML patients, whereas RUNX1 (20%) was the most common mutation in blast phase. Compared with wild-type ASXL1, CP-CML with mutant ASXL1 was associated with worse event-free survival (EFS) (median of 32.8 vs 88.3 months; P = 0.002) and failure-free survival (median of 13.8 vs 57.8 months; P = 0.04). In a multivariate analysis, ASXL1 mutation was the only independent risk factor associated with worse EFS in chronic phase CML with a hazard ratio of 4.25 (95% CI 1.59-11.35, P = 0.004). In conclusion, mutations in ASXL1 are associated with worse outcomes when detected in chronic phase CML.
| S-EPMC9616867 | biostudies-literature
Project description:Accurate prognostic stratification of patients can provide guidance for personalized therapy. Many prognostic models for acute myeloid leukemia (AML) have been reported, but most have considerable inaccuracies due to contained variables with insufficient capacity of predicting survival and lack of adequate verification. Here, 235 genes strongly related to survival in AML were systematically identified through univariate Cox regression analysis of eight independent AML datasets. Pathway enrichment analysis of these 235 genes revealed that the IL-2/STAT5 signaling pathway was the most highly enriched. Through Cox proportional-hazards regression model and stepwise algorithm, we constructed a six-gene STAT5-associated signature based on the most robustly survival-related genes related to the IL-2/STAT5 signaling pathway. Good prognostic performance was observed in the training cohort (GSE37642-GPL96), and the signature was validated in seven other validation cohorts. As an independent prognostic factor, the STAT5-associated signature was positively correlated with patient age and ELN2017 risk levels. An integrated score based on these three prognostic factors had higher prognostic accuracy than the ELN2017 risk category. Characterization of immune cell infiltration indicated that impaired B-cell adaptive immunity, immunosuppressive effects, serious infection, and weakened anti-inflammatory function tended to accompany high-risk patients. Analysis of in-house clinical samples revealed that the STAT5-assocaited signature risk scores of AML patients were significantly higher than those of healthy people. Five chemotherapeutic drugs that were effective in these high-risk patients were screened in silico. Among the five drugs, MS.275, a known HDAC inhibitor, selectively suppressed the proliferation of cancer cells with high STAT5 phosphorylation levels in vitro. Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments.
| S-EPMC8847395 | biostudies-literature
Project description:IntroductionAcute myeloid leukemia (AML) is an aggressive blood cancer with high heterogeneity and poor prognosis. Although the metabolic reprogramming of nicotinamide adenine dinucleotide (NAD) has been reported to play a pivotal role in the pathogenesis of acute myeloid leukemia (AML), the prognostic value of NAD metabolism and its correlation with the immune microenvironment in AML remains unclear.MethodsWe utilized our large-scale RNA-seq data on 655 patients with AML and the NAD metabolism-related genes to establish a prognostic NAD metabolism score based on the sparse regression analysis. The signature was validated across three independent datasets including a total of 1,215 AML patients. ssGSEA and ESTIMATE algorithms were employed to dissect the tumor immune microenvironment. Ex vivo drug screening and in vitro experimental validation were performed to identify potential therapeutic approaches for the high-risk patients. In vitro knockdown and functional experiments were employed to investigate the role of SLC25A51, a mitochondrial NAD+ transporter gene implicated in the signature.ResultsAn 8-gene NAD metabolism signature (NADM8) was generated and demonstrated a robust prognostic value in more than 1,800 patients with AML. High NADM8 score could efficiently discriminate AML patients with adverse clinical characteristics and genetic lesions and serve as an independent factor predicting a poor prognosis. Immune microenvironment analysis revealed significant enrichment of distinct tumor-infiltrating immune cells and activation of immune checkpoints in patients with high NADM8 scores, acting as a potential biomarker for immune response evaluation in AML. Furthermore, ex vivo drug screening and in vitro experimental validation in a panel of 9 AML cell lines demonstrated that the patients with high NADM8 scores were more sensitive to the PI3K inhibitor, GDC-0914. Finally, functional experiments also substantiated the critical pathogenic role of the SLC25A51 in AML, which could be a promising therapeutic target.ConclusionOur study demonstrated that NAD metabolism-related signature can facilitate risk stratification and prognosis prediction in AML and guide therapeutic decisions including both immunotherapy and targeted therapies.
| S-EPMC11222388 | biostudies-literature
Project description:The role of mitochondrial DNA (mt-DNA) changes, especially those in the regulatory D-loop region in Acute Myeloid Leukemia (AML) remains investigational. Consecutive 151 de novo pediatric AML patients, (≤18 yr) were prospectively enrolled from June 2013-August 2016, to assess the prognostic impact of mt-DNA D-loop variations (somatic/germline) on survival. For each patient, D-loop region was sequenced on baseline bone marrow and buccal swab, and mother's blood sample. In 151 AML subjects, 1490 variations were found at 237 positions; 80.9% were germline and 19.1% somatic. The mean number of variations per position was 6.3. Variations with frequency ≥6 were analyzed for their impact on survival and 4 categories were created, namely "somatic-protective", "somatic-hazardous", "germline-protective" and "germline- hazardous". Although, somatic-protective could not predict event free survival (EFS) or overall survival (OS), somatic-hazardous [(OS) HR = 2.33, p = 0.06] and germline-hazardous [(OS) HR = 2.85, p < 0.01] significantly predicted OS and EFS. Notably, the germline-protective, could significantly predict EFS (HR = 0.31, p = 0.03) and OS (HR = 0.19, p < 0.01), only when variations at ≥2 positions were present. On multivariate analysis, three positions namely 16111, 16126, 16362 and karyotype were found to be predictive of EFS. A prognostic index (PI) was developed using nomogram PI = (0.8*karyotype) + (1.0*c16111) + (0.7*t16362) + (1.2*t16126). Hazard ratio for EFS increased significantly with increasing PI reaching to a maximum of 3.3 (p < 0.01). In conclusion, the impact of mt-DNA D-loop variations on outcomes in pediatric AML depends on their nature (germline/somatic), position and mutational burden, highlighting their potential role as evolving prognostic biomarkers.
| S-EPMC6407682 | biostudies-literature