Identification of RHOBTB2 aberration as an independent prognostic indicator in acute myeloid leukemia.
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ABSTRACT:
SUBMITTER: Liu P
PROVIDER: S-EPMC8221349 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe overexpression of ALOX5AP has been observed in many types of cancer and has been identified as an oncogene. However, its role in acute myeloid leukemia (AML) has not been extensively studied. This study aimed to identify the expression and methylation patterns of ALOX5AP in bone marrow (BM) samples of AML patients, and further explore its clinical significance.MethodsEighty-two de novo AML patients and 20 healthy donors were included in the study. Meanwhile, seven public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were included to confirm the alteration of ALOX5AP. Receiver operating characteristic (ROC) curve analysis was applied to determine the discriminative capacity of ALOX5AP expression to discriminate AML. The prognostic value of ALOX5AP was identified by the Kaplan-Meier method and log-rank test. It was further validated in four independent cohorts (n = 1186). Significantly different genes associated with ALOX5AP expression were subsequently compared by LinkedOmics, and Metascape database.ResultsThe level of ALOX5AP expression was significantly increased in bone marrow cells of AML patients compared with healthy donors (P < 0.05). ROC curve analysis suggested that ALOX5AP expression might be a potential biomarker to discriminate AML from controls. ALOX5AP overexpression was associated with decreased overall survival (OS) in AML according to the TCGA data (P = 0.006), which was validated by other four independent cohorts. DNA methylation levels of ALOX5AP were significantly lower in AML patients compared to normal samples (P < 0.05), as confirmed in the Diseasemeth database and the independent cohort GSE63409. ALOX5AP level was positively associated with genes with proleukemic effects such as PAX2, HOX family, SOX11, H19, and microRNAs that act as oncogenes in leukemia, such as miR125b, miR-93, miR-494, miR-193b, while anti-leukemia-related genes and tumor suppressor microRNAs such as miR-582, miR-9 family and miR-205 were negatively correlated.ConclusionALOX5AP overexpression, associated with its hypomethylation, predicts poorer prognosis in AML.
| S-EPMC10667204 | biostudies-literature
Project description:HES1 is the target of Notch signaling which is reported to affect cell differentiation and maintain the cells in G0 phase in various tissues including the hematopoietic tissue. HES1 expression appears to be an independent prognostic factor for survival in a heterogeneous group of acute myeloid leukemia (AML) patients. To better assess its significance, we analyzed HES1 expression in a group of non-core binding factor AML patients and correlated its expression with the overall survival and relapse-free survival of AML patients. First, we detected the messenger RNA expression of HES1 in 40 patients with AML by real-time polymerase chain reaction. The top 50% of AML cases with the high HES1 expression were compared with the rest of the AML cohort. Overall survival was calculated from the date of diagnosis until the date of death from any cause or until the date of final follow-up. Relapse-free survival was determined for responders from the time of diagnosis until relapse or death from any cause. We showed that the lower-expression group had a shorter overall survival time and shorter relapse-free survival time compared with those of the high-expression group (37.6±1.6 versus 54.0±1.3 months, 28.6±1.8 months versus 44.8±2.1 months, respectively, P<0.05), and Cox regression showed that HES1 was an independent prognostic factor. In all, we conclude that expression of HES1 is a useful prognostic factor for patients with non-core binding factor AML.
| S-EPMC4410902 | biostudies-other
Project description:BackgroundIdentifying reliable predictive markers is important to make therapeutic decisions, and determine the prognosis for acute myeloid leukemia (AML) patients. However, approximately 50% patients could not be accurately predicted by existing risk factors. It is necessary to identify novel prognostic factors to subdivide the intermediate-risk group or patients without any cytogenetic and molecular abnormalities.MethodsKaplan-Meier and Cox regression were used for survival analyses in three independent AML datasets. Analyses integrating both bioinformatics and ChIP-qPCR experiments were performed to explore the role of CEBPE in regulating the expression of known prognostic factors.ResultsCEBPE expression was an independent predictor for both overall survival (OS) and event-free survival (EFS) of AML patients. Moreover, low-expression of CEBPE was found to be associated with high relapse rate. We also proved that differential expression of CEBPE stratified the wild-type patients of multiple genes into good and poor outcomes. In addition, the results showed that no obvious improvement was achieved by allogeneic transplantation in CEBPE high-expressed group, while the survival rate (both OS and EFS) was significantly increased in transplanted patients that with low expression of CEBPE. Finally, we found that CEBPE might regulate the expression of known prognostic factors by localizing on their promoters.ConclusionOur findings indicated that CEBPE expression was an independent prognostic factor for AML survival, relapse and allogeneic transplantation, which will provide useful information for outcome prediction and therapeutic decisions.
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Project description:BackgroundObesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated.ResultsIn the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML.ConclusionsOur findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.
| S-EPMC7824952 | biostudies-literature
Project description:The tumor microenvironment (TME) has a strong influence on the progression, therapeutic response, and clinical outcome of acute myeloid leukemia (AML), one of the most common hematopoietic malignancies in adults. In this study, we identified TME-related genes associated with AML prognosis. Gene expression profiles from AML patients were downloaded from TCGA database, and immune and stromal scores were calculated using the ESTIMATE algorithm. Immune scores were correlated with clinical features such as FAB subtypes and patient's age. After categorizing AML cases into high and low score groups, an association between several differentially expressed genes (DEGs) and overall survival was identified. Functional enrichment analysis of the DEGs showed that they were primarily enriched in the immune response, inflammatory response, and cytokine activity, and were involved in signaling processes related to hematopoietic cell lineage, B cell receptor, and chemokine pathways. Two significant modules, dominated respectively by CCR5 and ITGAM nodes, were identified from the PPI network, and 20 hub genes were extracted. A total of 112 DEGs correlated with poor overall survival of AML patients, and 11 of those genes were validated in a separate TARGET-AML cohort. By identifying TME-associated genes, our findings may lead to improved prognoses and therapies for AML.
| S-EPMC6914404 | biostudies-literature
Project description:Hematological malignancies possess a distinctive immunologic microenvironment compared with solid tumors. Here, using an established computational algorithm (CIBERSORT), we systematically analyzed the overall distribution of 22 tumor-infiltrating leukocyte (TIL) populations in more than 2000 bone marrow (BM) samples from 5 major hematological malignancies and healthy controls. Focusing on significantly altered TILs in acute myeloid leukemia (AML), we found that patients with AML exhibited increased frequencies of M2 macrophages, compared to either healthy controls or the other four malignancies. High infiltration of M2 macrophages was associated with poor outcome in AML. Further analysis revealed that CD206, a M2 marker gene, could faithfully reflect variation in M2 fractions and was more highly expressed in AML than normal controls. High CD206 expression predicted inferior overall survival (OS) and event-free survival (EFS) in two independent AML cohorts. Among 175 patients with intermediate-risk cytogenetics, the survival still differed greatly between low and high CD206 expressers (OS; P < .0001; 3-year rates, 56% v 32%; EFS; P < .001; 3-year rates, 47% v 25%). When analyzed in a meta-analysis, CD206 as a continuous variable showed superior predictive performance than classical prognosticators in AML (BAALC, ERG, EVI1, MN1, and WT1). In summary, M2 macrophages are preferentially enriched in AML. The M2 marker CD206 may serve as a new prognostic marker in AML.
| S-EPMC6959428 | biostudies-literature
Project description:BackgroundTripartite motif (TRIM)-62 is a putative tumor suppressor gene whose role in leukemia is unknown.Materials and methodsWe evaluated the effect of TRIM62 protein expression in patients with acute myeloid leukemia (AML). We used reverse-phase protein array methodology to determine TRIM62 levels in leukemia-enriched protein samples from 511 patients newly diagnosed with AML.ResultsTRIM62 levels in AML cells were significantly lower than in normal CD34-positive cells, suggesting that TRIM62 loss might be involved in leukemogenesis, but was not associated with specific karyotypic abnormalities or Nucleophosmin (NPM1), Fms-like Tyrosine Kinase-3 (FLT3), or rat sarcoma viral oncogene (RAS) mutational status. Low TRIM62 levels were associated with shorter complete remission duration and significantly shorter event-free and overall survival rates, particularly among patients with intermediate-risk cytogenetics. In that AML subgroup, age and TRIM62 levels were the most powerful independent prognostic factors for survival. TRIM62 protein levels further refined the risk associated with NPM1 and FLT3 mutational status. TRIM62 loss was associated with altered expression of proteins involved in leukemia stem cell homeostasis (β-catenin and Notch), cell motility, and adhesion (integrin-β3, ras-related C3 botulinum toxin substrate [RAC], and fibronectin), hypoxia (Hypoxia-inducible factor 1-alpha [HIF1α], egl-9 family hypoxia-inducible factor 1 [Egln1], and glucose-regulated protein, 78 kDa [GRP78]), and apoptosis (B-cell lymphoma-extra large (BclXL) and caspase 9).ConclusionLow TRIM62 levels, consistent with a tumor suppressor role, represent an independent adverse prognostic factor in AML.
| S-EPMC4560255 | biostudies-literature
Project description:Intermediate-risk acute myeloid leukemia (IR-AML) is the largest subgroup of AML patients and is highly heterogeneous. Whereas adverse and favourable risk patients have well-established treatment protocols, IR-AML patients have not. It is, therefore, crucial to find novel factors that stratify this subgroup to implement risk-adapted strategies. The CAS (Crk-associated substrate) adaptor protein family regulates cell proliferation, survival, migration and adhesion. Despite its association with metastatic dissemination and prognosis of different solid tumors, the role of these proteins in hematological malignancies has been scarcely evaluated. Nevertheless, previous work has established an important role for the CAS family members NEDD9 or BCAR1 in the migratory and dissemination capacities of myeloid cells. On this basis, we hypothesized that NEDD9 or BCAR1 expression levels could associate with survival in IR-AML patients and become new prognostic markers. To that purpose, we assessed BCAR1 and NEDD9 gene expression in a cohort of 73 adult AML patients validating the results in an independent cohort (n = 206). We have identified NEDD9, but not BCAR1, as a new a marker for longer overall and disease-free survival, and for lower cumulative incidence of relapse. In summary, NEDD9 gene expression is an independent prognostic factor for favourable prognosis in IR-AML patients.
| S-EPMC5652681 | biostudies-literature
Project description:BackgroundGlutathione peroxidases (GPXs) are an enzyme family with peroxidase activity. Abnormal GPX expression is associated with carcinogenesis. However, the potential role of the GPX gene family in acute myeloid leukemia (AML) remains to be comprehensively examined.MethodsWe analyzed GPX mRNA expression levels and determined the correlation between gene expression and the prognostic value via multiple universally acknowledged databases including the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), PROGgeneV2, UALCAN, Cancer Cell Line Encyclopedia (CCLE), and The European Bioinformatics Institute (EMBL-EBI) databases. The functional network of differentially expressed GPXs was investigated via the NetworkAnalyst platform. Correlated genes as well as kinase, microRNA (miRNA), and transcription factor (TF) targets were identified using LinkedOmics.ResultsWe observed that the transcriptional expression levels of GPX-1, -2, -4, -7, and -8 had significant difference between AML patients samples and normal samples, and that AML patients with high expression of GPX-1, -3, -4, and -7 were associated with poorer prognosis of overall survival (OS). Functional enrichment analysis showed that the differentially expressed GPXs were mainly enriched in response to oxidative stress, regulation of immune response, and inflammatory response, along with glutathione metabolism and ferroptosis. Overexpression of correlated genes, PSMB10, VPS13D, NDUFS8, ATP5D, POLR2E, and HADH were linked to adverse OS in AML. Regulatory network analysis indicated that differentially expressed GPXs regulated cell proliferation, cancer progression, apoptosis, and cell cycle signaling via pathways involving cancer-related kinases (such as DAPK1 and SRC), miRNAs (such as miR-202 and miR-181), and TFs (such as SRF and E2F1).ConclusionsOur findings offer novel insights into the differential expression and prognostic potential of the GPX family in AML, and lay a foundation for subsequent research of GPX's role in the carcinogenesis and regulatory network of AML.
| S-EPMC7327321 | 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