scholarly journals The Multi-Omic Prognostic Model of Oxidative Stress-Related Genes in Acute Myeloid Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Chao Dong ◽  
Naijin Zhang ◽  
Lijun Zhang
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Enrichment Analysis ◽  
Chemotherapeutic Agents ◽  
The Cancer Genome Atlas ◽  
Stress Genes ◽  
Acute Myeloid

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.

Identification of Aberrantly Methylated and Silenced Genes in Acute Myeloid Leukemia by Combined Methylation/expression Analysis

2020 ◽  
Author(s):  
Chao Guo ◽  
Qian-qian Ju ◽  
Chun-xia Zhang ◽  
Ming Gong ◽  
Ya-yue Gao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Subgroup Analysis ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Enrichment Analysis ◽  
Gene Expression Omnibus ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Aberrant Methylation ◽  
Acute Myeloid

Abstract Background Aberrant genomic methylation plays an important role in pathogenic process of acute myeloid leukemia (AML) by silencing tumor suppressor genes (TSG). While the key aberrantly methylated genes and related pathways have not been well understood yet, which we aimed to reveal by combined analysis of methylation and expression datasets. The prognostic significance was validated by survival analysis derived from TCGA database. Methods Micro-array data of GSE 15061 and GSE58477 were downloaded from Gene Expression Omnibus (GEO) database. The differentially methylated regions (DMR) and differentially expressed genes (DEG) were identified using R program (R 3.6.1). Over-representation analysis was performed to obtain the enriched biological processes and pathways. Cox hazards analysis was employed to select the genes significantly associated with AML survival, using the data derived from the Cancer Genome Atlas (TCGA) database. Subgroup analysis, regarding induction type, was conducted to identify biomarkers for HMA treatment. Furthermore, SYNJ2 associated genome-wide gene/miRNA expression and methylation profile were explored. Results A total of 198 aberrant methylation related underexpressed genes were identified. Univariable analysis revealed methylation level of 6 out of 198 genes (CORO1A/MPO/SYNJ2/EHD1/GAS2L1/SLC11A1) were significantly associated with AML survival. SYNJ2 methylation was an independent predictor for OS. Notably, subgroup analysis revealed hypermethylation of CORO1A predicted better OS in HMA group. Further gene set enrichment analysis indicated SYNJ2-associated activation of PI3K-Akt/NF-kappaB/JAK-STAT signaling and checkpoint pathway. The microRNAs, such as miR217/miR485-3p/miR-889-3p, were downregulated in SYNJ2-hypermethylated group, leading to potential HOXA13 upregulation. Conclusion The prognostic methylation signature was revealed in our studies, and SYNJ2 was proved as an independent prognostic factor. Methylation of CORO1A may serve as biomarker for HMA treatment in AML.

scholarly journals Association Analyses of TP53 Mutation With Prognosis, Tumor Mutational Burden, and Immunological Features in Acute Myeloid Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiang-mei Wen ◽  
Zi-jun Xu ◽  
Ye Jin ◽  
Pei-hui Xia ◽  
Ji-chun Ma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Enrichment Analysis ◽  
Predictive Biomarker ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Association Analyses ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease related to a broad spectrum of molecular alterations. The successes of immunotherapies treating solid tumors and a deeper understanding of the immune systems of patients with hematologic malignancies have promoted the development of immunotherapies for the treatment of AML. And high tumor mutational burden (TMB) is an emerging predictive biomarker for response to immunotherapy. However, the association of gene mutation in AML with TMB and immunological features still has not been clearly elucidated. In our study, based on The Cancer Genome Atlas (TCGA) and BeatAML cohorts, 20 frequently mutated genes were found to be covered by both datasets in AML. And TP53 mutation was associated with a poor prognosis, and its mutation displayed exclusiveness with other common mutated genes in both datasets. Moreover, TP53 mutation correlated with TMB and the immune microenvironment. Gene Set Enrichment Analysis (GSEA) showed that TP53 mutation upregulated signaling pathways involved in the immune system. In summary, TP53 mutation is frequently mutated in AML, and its mutation is associated with dismal outcome, TMB, and immunological features, which may serve as a biomarker to predict immune response in AML.

scholarly journals Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ting-juan Zhang ◽  
Zi-jun Xu ◽  
Yu Gu ◽  
Ji-chun Ma ◽  
Xiang-mei Wen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Related Gene ◽  
Targeted Bisulfite Sequencing ◽  
Specific Pcr ◽  
Frequent Event ◽  
Acute Myeloid

Abstract Background Obesity 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. Results In 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. Conclusions Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.

scholarly journals Increased Oxidative Stress in Acute Myeloid Leukemia Patients after Red Blood Cell Transfusion, but Not Platelet Transfusion, Results Mainly from the Oxidative/Nitrative Protein Damage: An Exploratory Study

2021 ◽  
Vol 10 (7) ◽  
pp. 1349
Author(s):  
Kamila Czubak-Prowizor ◽  
Jacek Trelinski ◽  
Paulina Stelmach ◽  
Piotr Stelmach ◽  
Agnieszka Madon ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Exploratory Study ◽  
Myeloid Leukemia ◽  
Thiobarbituric Acid ◽  
Red Blood Cell Transfusion ◽  
Packed Red Blood Cells ◽  
Chronic Oxidative Stress ◽  
Total Antioxidant ◽  
Acute Myeloid

Chronic oxidative stress (OS) can be an important factor of acute myeloid leukemia (AML) progression; however, there are no data on the extent/consequence of OS after transfusion of packed red blood cells (pRBCs) and platelet concentrates (PCs), which are commonly used in the treatment of leukemia-associated anemia and thrombocytopenia. We aimed to investigate the effects of pRBC/PC transfusion on the OS markers, i.e., thiol and carbonyl (CO) groups, 3-nitrotyrosine (3-NT), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGE), total antioxidant capacity (TAC), SOD, GST, and LDH, in the blood plasma of AML patients, before and 24 h post-transfusion. In this exploratory study, 52 patients were examined, of which 27 were transfused with pRBCs and 25 with PCs. Age-matched healthy subjects were also enrolled as controls. Our results showed the oxidation of thiols, increased 3-NT, AGE levels, and decreased TAC in AML groups versus controls. After pRBC transfusion, CO groups, AGE, and 3-NT significantly increased (by approximately 30, 23, and 35%; p < 0.05, p < 0.05, and p < 0.01, respectively) while thiols reduced (by 18%; p < 0.05). The PC transfusion resulted in the raise of TBARS and AGE (by 45%; p < 0.01 and 31%; p < 0.001), respectively). Other variables showed no significant post-transfusion changes. In conclusion, transfusion of both pRBCs and PCs was associated with an increased OS; however, transfusing the former may have more severe consequences, since it is associated with the irreversible oxidative/nitrative modifications of plasma proteins.

scholarly journals ATM/G6PD-driven redox metabolism promotes FLT3 inhibitor resistance in acute myeloid leukemia

2016 ◽  
Vol 113 (43) ◽  
pp. E6669-E6678 ◽  
Author(s):  
Mark A. Gregory ◽  
Angelo D’Alessandro ◽  
Francesca Alvarez-Calderon ◽  
Jihye Kim ◽  
Travis Nemkov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Oxidative Stress ◽  
Flt3 Inhibitor ◽  
A Genome ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

Deregulation of Signaling Pathways in Acute Myeloid Leukemia

2008 ◽  
Vol 35 (4) ◽  
pp. 336-345 ◽  
Author(s):  
Claudia Scholl ◽  
D. Gary Gilliland ◽  
Stefan Fröhling
Keyword(s):  
Acute Myeloid Leukemia ◽  
Signaling Pathways ◽  
Myeloid Leukemia ◽  
Acute Myeloid

A novel prognostic model in elderly patients with acute myeloid leukemia: results of 909 patients entered into the prospective AML96 trial

Blood ◽  
2010 ◽  
Vol 116 (6) ◽  
pp. 971-978 ◽  
Author(s):  
Christoph Röllig ◽  
Christian Thiede ◽  
Martin Gramatzki ◽  
Walter Aulitzky ◽  
Heinrich Bodenstein ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Risk Model ◽  
Cox Model ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Prognostic Groups ◽  
Acute Myeloid

Abstract We present an analysis of prognostic factors derived from a trial in patients with acute myeloid leukemia older than 60 years. The AML96 trial included 909 patients with a median age of 67 years (range, 61-87 years). Treatment included cytarabine-based induction therapy followed by 1 consolidation. The median follow-up time for all patients is 68 months (5.7 years). A total of 454 of all 909 patients reached a complete remission (50%). Five-year overall survival (OS) and disease-free survival were 9.7% and 14%, respectively. Multivariate analyses revealed that karyotype, age, NPM1 mutation status, white blood cell count, lactate dehydrogenase, and CD34 expression were of independent prognostic significance for OS. On the basis of the multivariate Cox model, an additive risk score was developed that allowed the subdivision of the largest group of patients with an intermediate-risk karyotype into 2 groups. We are, therefore, able to distinguish 4 prognostic groups: favorable risk, good intermediate risk, adverse intermediate risk, and high risk. The corresponding 3-year OS rates were 39.5%, 30%, 10.6%, and 3.3%, respectively. The risk model allows further stratification of patients with intermediate-risk karyotype into 2 prognostic groups with implications for the therapeutic strategy. This study was registered at www.clinicaltrials.gov as #NCT00180115.

scholarly journals A robust and rapid xenograft model to assess efficacy of chemotherapeutic agents for human acute myeloid leukemia

2015 ◽  
Vol 5 (3) ◽  
pp. e297-e297 ◽  
Author(s):  
E Saland ◽  
H Boutzen ◽  
R Castellano ◽  
L Pouyet ◽  
E Griessinger ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Xenograft Model ◽  
Chemotherapeutic Agents ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid
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