Dataset Information

The Identification of APOBEC3G as a Potential Prognostic Biomarker in Acute Myeloid Leukemia and a Possible Drug Target for Crotonoside.

ABSTRACT: The apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G) converts cytosine to uracil in DNA/RNA. Its role in resisting viral invasion has been well documented. However, its expression pattern and potential function in AML remain unclear. In this study, we carried out a bioinformatics analysis and revealed that the expression of APOBEC3G was significantly upregulated in AML, and high expression of APOBEC3G was significantly associated with short overall survival (OS). APOBEC3G expression was especially increased in non-M3AML, and correlated with the unfavorable cytogenetic risks. Additionally, Cox regression analyses indicated APOBEC3G is a hazard factor that cannot be ignored for OS of AML patients. In molecular docking simulations, the natural product crotonoside was found to interact well with APOBEC3G. The expression of APOBEC3G is the highest in KG-1 cells, and the treatment with crotonoside can reduce the expression of APOBEC3G. Crotonoside can inhibit the viability of different AML cells in vitro, arrest KG-1 and MV-4-11 cells in the S phase of the cell cycle and affect the expression of cycle-related proteins, and induce cell apoptosis. Therefore, APOBEC3G could be a potential drug target of crotonoside, and crotonoside can be considered as a lead compound for APOBEC3G inhibition in non-M3 AML.

SUBMITTER: Ma C

PROVIDER: S-EPMC9503540 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The Identification of APOBEC3G as a Potential Prognostic Biomarker in Acute Myeloid Leukemia and a Possible Drug Target for Crotonoside.

Ma Chenchen C Liu Peng P Cui Siyuan S Gao Chang C Tan Xing X Liu Zhaopeng Z Xu Ruirong R

Molecules (Basel, Switzerland) 20220907 18

The apolipoprotein B mRNA editing enzyme catalytic subunit 3G (APOBEC3G) converts cytosine to uracil in DNA/RNA. Its role in resisting viral invasion has been well documented. However, its expression pattern and potential function in AML remain unclear. In this study, we carried out a bioinformatics analysis and revealed that the expression of APOBEC3G was significantly upregulated in AML, and high expression of APOBEC3G was significantly associated with short overall survival (OS). APOBEC3G exp ...[more]

PMID: 36144542

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Project description:Acute myeloid leukemia (AML) is a clonal hematological malignancy with high mortality rates. The identification of novel markers is urgent for AML. Cytohesins are a subfamily of guanine nucleotide exchange factors activating the ADP-ribosylation factor family GTPases. While the important roles of cytohesins have been reported in various cancers, their function in AML remains unclear. The present study aimed to explore the prognostic impact of cytohesin-4 (CYTH4) and the underlying molecular functions. RNA sequencing and AML clinical data were obtained from The Cancer Genome Atlas and Gene Expression Omnibus databases to investigate gene expression and survival. Using the R software, differentially expressed genes were identified between the high- and the low-CYTH4 group. Functional enrichment analysis was conducted by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analyses. The CIBERSORTx tool was used to explore the proportions of different immune cell types. The molecular function of CYTH4 was also validated in vitro by examining cell growth, cell cycle, apoptosis and colony-forming ability. CYTH4 was significantly upregulated in AML compared with other cancers and normal tissues. High CYTH4 expression was associated with high white blood count (P=0.004) and higher risk status (P<0.001). Patients with high CYTH4 expression had poor overall survival (OS; HR=2.19; 95% CI, 1.40-3.44; P=0.0006; high vs. low) and event-free survival (EFS; HR=2.32; 95% CI, 1.43-3.75; P=0.0006; high vs. low), and these patients could benefit from transplantation (HR=0.29; 95% CI, 0.18-0.47; P<0.0001; transplantation vs. chemotherapy). Multivariate analysis showed that high CYTH4 expression was independently associated with inferior OS (HR=2.49; 95% CI, 1.28-4.83; P=0.007) and EFS (HR=2.56; 95% CI, 1.48-4.42; P=0.001). Functional analysis showed that CYTH4 was involved in immunoregulation. In vitro validation showed knockdown of CYTH4 adversely affected cell growth and induced cell apoptosis, while overexpression of CYTH4 enhanced cell growth. Taken together, CYTH4 is expressed at high levels in AML and can potentially function as a prognostic biomarker.

Project description:Although the implication of BCL3 has been disclosed in human chronic lymphocytic leukemia as well as other solid tumors, the diagnostic and prognostic of BCL3 expression in acute myeloid leukemia (AML) remains largely unclear. In this study, we isolated total RNA from bone marrow mononuclear cells collected from 101 de novo AML patients and 27 healthy donors. After reverse transcription, quantitative real-time PCR was performed to detect BCL3 expression level. BCL3 mRNA level was significantly down-regulated in BMMCs of AML patients compared with healthy controls (P = 0.0015). BCL3 was showed a higher level in AML patients with poor-risk karyotypes than that of in patients with favorable/intermediate-risk karyotypes (P = 0.014). ROC analysis demonstrated that BCL3 could effectively differentiate AML patients from normal controls. Among the French-American-British (FAB) subtypes, the frequency of low BCL3 expression in M2 subtypes is significantly higher than that of in the other subtypes M1/M4/M5/M6/M7 (P = 0.006), and mildly lower in myelomonocytic/monocytic subtypes M4/M5 (P = 0.064) than those in M1/M2/M6/M7 subtypes. Chromosome analysis revealed that BCL3low patients had a remarkably higher frequency of t (8;21) abnormality (P = 0.0047) and lower frequency of normal karyotype (P = 0.0059) than BCL3high patients. BCL3high patients showed a significantly higher frequency of FLT3-ITD mutation (P = 0.028) and lower frequency of C-Kit mutation (P = 0.0232) than BCL3low patients. Although there were no significant differences in complete remission and overall survival between BCL3low and BCL3high groups, patients with high BCL3 expression markedly shorter overall survival (OS, P = 0.049), relapse-free survival (RFS, P = 0.027) and disease-free survival (DFS, P = 0.042) in M2 AML than low BCL3 expression patients. Additionally, in AMLs of M2 subtype, high BCL3 expression patients had markedly lower complete remission (CR) rate (P = 0.0317) after the second induction treatment than patients with BCL3 low expression. Thus, these findings indicated that BCL3 appeared as a promising molecular biomarker of pediatric acute myeloid leukemia with unfavorable prognosis.

Dataset Information

The Identification of APOBEC3G as a Potential Prognostic Biomarker in Acute Myeloid Leukemia and a Possible Drug Target for Crotonoside.

Publications

The Identification of APOBEC3G as a Potential Prognostic Biomarker in Acute Myeloid Leukemia and a Possible Drug Target for Crotonoside.

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