TMEM18: A Novel Prognostic Marker in Acute Myeloid Leukemia

Background: Certain nuclear envelope proteins are associated with important cancer cell characteristics, including migration and proliferation. Abnormal expression of and genetic changes in nuclear envelope proteins have been reported in acute myeloid leukemia (AML) patients. Transmembrane protein 18 (TMEM18), a nuclear envelope protein, is involved in neural stem cell migration and tumorigenicity. Methods: To examine the prognostic significance of TMEM18 in AML patients, we analyzed an AML cohort from The Cancer Genome Atlas (TCGA, n = 142). Results: Kaplan-Meier survival analysis revealed that TMEM18 overexpression was associated with a better AML prognosis with good discrimination (p = 0.019). Interestingly, this ability to predict the prognosis was significant in male AML patients, but not in female ones. C-index and area-under-the-curve analyses further supported this discriminative ability and multivariate analysis confirmed its prognostic significance (p = 0.00347). Correlation analysis revealed that TMEM18 had a statistically significant positive correlation with nuclear envelop protein 133 (NUP133), NUP35, NUP54, NUP62, and NUP88. Conclusion: Because the current AML prognostic factors do not take mRNA expression into consideration unlike other cancers, the development of mRNA-based prognostic factors would be beneficial for accurate prediction of the survival of AML patients. Therefore, TMEM18 gene is a potential biomarker for AML.

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The establishment of a prognostic scoring model based on the new tumor immune microenvironment classification in acute myeloid leukemia

BMC Medicine ◽

10.1186/s12916-021-02047-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Tiansheng Zeng ◽

Longzhen Cui ◽

Wenhui Huang ◽

Yan Liu ◽

Chaozeng Si ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Model ◽

Prognostic Significance ◽

The Cancer Genome Atlas ◽

Prognostic Models ◽

Clustering Methods ◽

Immune Microenvironment ◽

Tumor Immune Microenvironment ◽

Acute Myeloid

Abstract Background The high degree of heterogeneity brought great challenges to the diagnosis and treatment of acute myeloid leukemia (AML). Although several different AML prognostic scoring models have been proposed to assess the prognosis of patients, the accuracy still needs to be improved. As important components of the tumor microenvironment, immune cells played important roles in the physiological functions of tumors and had certain research value. Therefore, whether the tumor immune microenvironment (TIME) can be used to assess the prognosis of AML aroused our great interest. Methods The patients’ gene expression profile from 7 GEO databases was normalized after removing the batch effect. TIME cell components were explored through Xcell tools and then hierarchically clustered to establish TIME classification. Subsequently, a prognostic model was established by Lasso-Cox. Multiple GEO databases and the Cancer Genome Atlas dataset were employed to validate the prognostic performance of the model. Receiver operating characteristic (ROC) and the concordance index (C-index) were utilized to assess the prognostic efficacy. Results After analyzing the composition of TIME cells in AML, we found infiltration of ten types of cells with prognostic significance. Then using hierarchical clustering methods, we established a TIME classification system, which clustered all patients into three groups with distinct prognostic characteristics. Using the differential genes between the first and third groups in the TIME classification, we constructed a 121-gene prognostic model. The model successfully divided 1229 patients into the low and high groups which had obvious differences in prognosis. The high group with shorter overall survival had more patients older than 60 years and more poor-risk patients (both P< 0.001). Besides, the model can perform well in multiple datasets and could further stratify the cytogenetically normal AML patients and intermediate-risk AML population. Compared with the European Leukemia Net Risk Stratification System and other AML prognostic models, our model had the highest C-index and the largest AUC of the ROC curve, which demonstrated that our model had the best prognostic efficacy. Conclusion A prognostic model for AML based on the TIME classification was constructed in our study, which may provide a new strategy for precision treatment in AML.

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The Prognostic Significance of PDE7B in Cytogenetically Normal Acute Myeloid Leukemia

Scientific Reports ◽

10.1038/s41598-019-53563-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Ling Cao ◽

Weilong Zhang ◽

Xiaoni Liu ◽

Ping Yang ◽

Jing Wang ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Proportional Hazards ◽

Expression Profiles ◽

Prognostic Significance ◽

Gene Expression Profiles ◽

Cox Proportional Hazards ◽

The Cancer Genome Atlas ◽

Acute Myeloid

AbstractAcute myeloid leukemia (AML) is a malignant hematological disease in which nearly half have normal cytogenetics. We have tried to find some significant molecular markers for this part of the cytogenetic normal AML, which hopes to provide a benefit for the diagnosis, molecular typing and prognosis prediction of AML patients. In the present study, we calculated and compared the gene expression profiles of cytogenetically normal acute myeloid leukemia (CN-AML) patients in database of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) and dataset Vizome (a total of 632 CN-AML samples), and we have demonstrated a correlation between PDE7B gene and CN-AML. Then we proceeded to a survival analysis and prognostic risk analysis between the expression levels of PDE7B gene and CN-AML patients. The result showed that the event-free survival (EFS) and overall survival (OS) were significantly shorter in CN-AML patients with high PDE7B levels in each dataset. And we detected a significantly higher expression level of PDE7B in the leukemia stem cell (LSC) positive group. The Cox proportional hazards regression model showed that PDE7B is an independent risk predictor for CN-AML. All results indicate that PDE7B is an unfavorable prognostic factor for CN-AML.

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Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation

BioMed Research International ◽

10.1155/2020/9321630 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Shuyi Chen ◽

Yimin Chen ◽

Jielun Lu ◽

Danyun Yuan ◽

Lang He ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Dna Methyltransferase ◽

Bioinformatics Analysis ◽

Genetic Alterations ◽

The Cancer Genome Atlas ◽

Pathway Enrichment Analysis ◽

Potential Biomarker ◽

Key Genes ◽

Acute Myeloid

Background. DNA methyltransferase 3 alpha (DNMT3A) mutation was one of the most frequent genetic alterations in acute myeloid leukemia (AML), which was associated with poor prognosis and appeared to be a potential biomarker. Herein, we aimed to identify the key genes and pathways involved in adult AML with DNMT3A mutations and to find possible therapeutic targets for improving treatment. Methods. The RNA sequencing datasets of 170 adult AML patients were obtained from The Cancer Genome Atlas (TCGA) database. EdgeR of the R platform was used to identify the differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape and DAVID. And protein-protein interaction (PPI) network and clustering modules were analyzed with the STRING database and Cytoscape software. Results. Mutated DNMT3A resulted in a shorter overall survival (OS) in AML patients and obviously associated with age, blast percentage in peripheral blood, and FLT3 mutation. A total of 283 DEGs were detected, of which 95 were upregulated and 188 were downregulated. GO term analysis showed that DEGs were significantly enriched in neutrophil degranulation, myeloid cell differentiation, stem cell proliferation, positive regulation of neurological system process, leukocyte migration, and tissue morphogenesis. KEGG pathway enrichment analysis indicated that the pathway of cancer, PI3K-Akt signaling pathway, and transcriptional misregulation in cancer may play a crucial role in DNMT3A mutation AML. Seven hub genes (BMP4, MPO, THBS1, APP, ELANE, HOXA7, and VWF) had a significant prognostic value. Conclusion. Bioinformatics analysis in the present study provided novel targets for early diagnosis and new strategies for treatment for AML with DNMT3A mutation.

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Multivariate analysis of prognostic factors in acute myeloid leukemia: value of clonogenic leukemic cell properties.

Journal of Clinical Oncology ◽

10.1200/jco.1989.7.6.738 ◽

1989 ◽

Vol 7 (6) ◽

pp. 738-746 ◽

Cited By ~ 31

Author(s):

A Delmer ◽

J P Marie ◽

D Thevenin ◽

M Cadiou ◽

F Viguié ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Multivariate Analysis ◽

Prognostic Factors ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Practical Interest ◽

Leukemic Cell ◽

European Organization ◽

Self Renewal ◽

Acute Myeloid

The initial clinical and biological parameters, including clonogenic leukemic cell (CFU-L) assay, were reviewed for their prognostic significance in a cohort of 188 adult patients with newly diagnosed untreated acute myeloid leukemia (AML). Almost all patients received induction therapy with daunorubicin (DNR) and cytarabine (Ara-C) according to the European Organization for Research and Treatment of Cancer (EORTC) AML 5 to AML 9 trials. Bone marrow samples from 116 representative patients were obtained for CFU-L assay with an efficiency percentage of 89.6%; 76 patients had a measurement of the CFU-L self-renewal capacity (second plating efficiency [PE2]) and 91 patients had CFU-L inhibition test after exposure to DNR and/or Ara-C. The prognostic significance of parameters such as age, hematological antecedent, WBC count, liver enlargement, and Auer rods is confirmed in the present study. Moreover, high platelet and polymorphonuclear counts appeared to be related to resistance to induction course. However, through multivariate analysis, CFU-L sensitivity to drugs and self-renewal capacity appeared to be major independent prognostic factors in AML. A low CFU-L inhibition in the presence of the DNR and Ara-C combination correlates with a poorer complete remission (CR) rate, but not with CR duration. Patients with the lower PE2 values experienced both higher CR rate and longer CR duration. The practical interest of CFU-L study remains to be defined but, at least, PE2 measurement could be considered in the future as a major variable in determining therapeutic aggressiveness.

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Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461

Blood ◽

10.1182/blood-2005-11-4354 ◽

2006 ◽

Vol 108 (1) ◽

pp. 63-73 ◽

Cited By ~ 219

Author(s):

Sherif S. Farag ◽

Kellie J. Archer ◽

Krzysztof Mrózek ◽

Amy S. Ruppert ◽

Andrew J. Carroll ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Prognostic Factors ◽

Complete Remission ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Multivariable Analysis ◽

Disease Free Survival ◽

Term Outcome ◽

Long Term Outcome ◽

Acute Myeloid

We investigated the relative prognostic significance of cytogenetics in 635 adult acute myeloid leukemia (AML) patients 60 years of age or older treated on front-line protocols. Classification trees and tree-structured survival analysis (TSSA) were used to identify important cytogenetic groups, and their prognostic significance was then assessed in multivariable analysis (MVA). Overall, 48.5% achieved complete remission (CR); 6.6% survived at 5 years. Complex karyotypes with at least 3 abnormalities (complex ≥ 3) and a group including “rare aberrations” predicted lower CR rates (25% and 30%) versus other patients (56%). Compared with complex ≥ 3, the odds of CR were significantly higher for noncomplex karyotypes without rare aberrations on MVA. Cytogenetically, complex ≥ 5 predicted inferior disease-free survival on TSSA, remaining significant on MVA together with white blood cell count (WBC), sex, and age. For survival, complex ≥ 5, rare aberrations, and core-binding factor (CBF) abnormalities were prognostic (P < .001), with 5-year survivals of 0%, 0%, and 19.4%, respectively, and 7.5% for remaining patients. Together with WBC, marrow blasts, sex, and age, the cytogenetic groups remained significant on MVA. In conclusion, pretreatment cytogenetics adds to other prognostic factors in older AML patients. Patients with complex ≥ 5 appear to benefit minimally from current treatment and are better suited for investigational therapy or supportive care. (Blood. 2006;108:63-73)

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

10.21203/rs.3.rs-87795/v1 ◽

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.

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