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. 2018 Aug;18(2):1473-1484.
doi: 10.3892/mmr.2018.9139. Epub 2018 Jun 6.

A three‑lncRNA Signature for Prognosis Prediction of Acute Myeloid Leukemia in Patients

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Free PMC article

A three‑lncRNA Signature for Prognosis Prediction of Acute Myeloid Leukemia in Patients

Fangce Wang et al. Mol Med Rep. .
Free PMC article

Abstract

Long non-coding RNAs (lncRNAs) are transcripts characterized by >200 nucleotides, without validated protein production. Previous studies have demonstrated that certain lncRNAs have a critical role in the initiation and development of acute myeloid leukemia (AML). In the present study, the subtype‑specific lncRNAs in AML was identified. Following the exclusion of the subtype‑specific lncRNAs, the prognostic value of lncRNAs was investigated and a three‑lncRNA expression‑based risk score [long intergenic non‑protein coding RNA 926, family with sequence similarity 30 member A and LRRC75A antisense RNA 1 (LRRC75A‑AS1)] was developed for AML patient prognosis prediction by analyzing the RNA‑seq data of AML patients from Therapeutically Available Research to Generate Effective Treatments (TARGET) and The Cancer Genome Atlas (TCGA) projects. In the training set obtained from TARGET, patients were divided into poor and favorable prognosis groups by the median risk score. The prognostic effectiveness of this lncRNA risk score was confirmed in the validation set obtained from TCGA by the same cut‑off. Furthermore, the lncRNA risk score was identified as an independent prognostic factor in the multivariate analysis. As further verification of the independent prognostic power of the lncRNA risk score, stratified analysis was performed by a cytogenetics risk group and revealed a consistent result. The prognostic predictive ability of the risk score was compared with the cytogenetics risk group by time‑dependent receiver operating characteristic curves analysis. It was revealed that the combination of the lncRNA risk score and cytogenetics risk group provided a higher prognostic value than a single prognostic factor. The present study also performed co‑expression analysis to predict the potential regulatory mechanisms of these lncRNAs in a cis/trans/competing endogenous RNA manner. The results suggested that LRRC75A‑AS1 was highly associated with the target genes of transcription factors tumor protein 53 and ETS variant 6. Overall, these results highlighted the use of the three‑lncRNA expression‑based risk score as a potential molecular biomarker to predict the prognosis in AML patients.

Figures

Figure 1.
Figure 1.
Flow chart of the protocol employed in the present study. TARGET, Therapeutically Available Research to Generate Effective Treatments; AML, acute myeloid leukemia; TCGA, The Cancer Genome Atlas; lncRNA, long non-coding RNA; ceRNA, competing endogenous RNA; ROC, receiver operating characteristic curves.
Figure 2.
Figure 2.
Expression profiles of lncRNAs with stable expression are presented in the heatmap. TARGET, Therapeutically Available Research to Generate Effective Treatments; TCGA, The Cancer Genome Atlas; lncRNA, long non-coding RNA; FAB, French-American-British system; FLT3/ITD, tyrosine kinase 3-internal tandem duplication; NPM, nucleophosmin; CEBPA, CCAAT/enhancer binding protein-α; WT1, Wilms tumor 1.
Figure 3.
Figure 3.
Box plot graphics were employed to illustrate the comparisons in lncRNAs expression between subgroups. (A) Expression of 6 FAB-M5 associated lncRNAs in the TARGET project. (B) Expression of 6 FAB-M5 associated lncRNAs in TCGA project. (C) Expression of 3 FLT3-itd associated lncRNAs, 2 NPM1 mutation associated lncRNAs and a CEBPA mutation associated lncRNA in the TARGET project. (D) Expression of 3 FLT3-itd associated lncRNAs, 2 NPM1 mutation associated lncRNAs and a CEBPA mutation associated lncRNA in TCGA project. (E) Expression of 3 inv (16) associated lncRNAs in the TARGET project. (F) Expression of 3 inv (16) associated lncRNAs in TCGA project. TARGET, Therapeutically Available Research to Generate Effective Treatments; TCGA, The Cancer Genome Atlas; lncRNA, long non-coding RNA; FAB, French-American-British system; wt, wild type; mut, mutation; FLT3-itd, tyrosine kinase 3-internal tandem duplication; NPM, nucleophosmin; CEBPA, CCAAT/enhancer binding protein-α; WT1, Wilms tumor 1.
Figure 3.
Figure 3.
Box plot graphics were employed to illustrate the comparisons in lncRNAs expression between subgroups. (A) Expression of 6 FAB-M5 associated lncRNAs in the TARGET project. (B) Expression of 6 FAB-M5 associated lncRNAs in TCGA project. (C) Expression of 3 FLT3-itd associated lncRNAs, 2 NPM1 mutation associated lncRNAs and a CEBPA mutation associated lncRNA in the TARGET project. (D) Expression of 3 FLT3-itd associated lncRNAs, 2 NPM1 mutation associated lncRNAs and a CEBPA mutation associated lncRNA in TCGA project. (E) Expression of 3 inv (16) associated lncRNAs in the TARGET project. (F) Expression of 3 inv (16) associated lncRNAs in TCGA project. TARGET, Therapeutically Available Research to Generate Effective Treatments; TCGA, The Cancer Genome Atlas; lncRNA, long non-coding RNA; FAB, French-American-British system; wt, wild type; mut, mutation; FLT3-itd, tyrosine kinase 3-internal tandem duplication; NPM, nucleophosmin; CEBPA, CCAAT/enhancer binding protein-α; WT1, Wilms tumor 1.
Figure 4.
Figure 4.
Random survival forests variable hunting analysis for event-free survival in the TARGET database. (A) The error rate of random survival forests model using all 25 potential prognostic lncRNAs as variables. (B) Variable importance values for predictors. (C) The error rate of random survival forests model using 1, 2 and 3 lncRNAs as variables. TARGET, Therapeutically Available Research to Generate Effective Treatments; lncRNA, long non-coding RNA.
Figure 5.
Figure 5.
Three-lncRNA based risk score distribution, patients' event-free survival status and a heatmap of the three lncRNA expression profiles. LncRNA, long non-coding RNA.
Figure 6.
Figure 6.
Kaplan-Meier estimates of the survival outcomes for patients using the three-lncRNA signature. (A) Kaplan-Meier curves of event-free survival for the TARGET AML set (n=340). (B) Kaplan-Meier curves of overall survival for the TARGET AML set (n=340). (C) Kaplan-Meier curves of event-free survival for the TCGA AML set (n=162). (D) Kaplan-Meier curves of overall survival for the TCGA AML set (n=162). LncRNA, long non-coding RNA; TARGET, Therapeutically Available Research to Generate Effective Treatments; TCGA, The Cancer Genome Atlas; AML, acute myeloid leukemia.
Figure 7.
Figure 7.
Stratification analyses of all patients adjusted to the cytogenetics risk group. (A) A Kaplan-Meier plot of the favorable risk status patients with AML (n=133). (B) The Kaplan-Meier plot of the intermediate risk status patients with AML (n=273). (C) The Kaplan-Meier plot of the poor risk status patients with AML (n=96). AML, acute myeloid leukemia.
Figure 8.
Figure 8.
ROC analysis of risk factors for survival prediction in the merged set. The area under the curve was calculated for ROC curves, and sensitivity and specificity were calculated to assess the score performance. ROC, receiver operating characteristic; lncRNA, long non-coding RNA.
Figure 9.
Figure 9.
(A) The co-expression network of the three lncRNAs. (B) Network of TP53 and ETV6 target genes associated with LRRC75A-AS1. (C) Competing endogenous RNA network of the three lncRNAs. Red nodes, mRNA; blue diamonds, lncRNA; green rectangle, microRNA. LncRNA, long non-coding RNA; TP53, tumor protein 53; ETV6, ETS variant 6; LRRC75A-AS1, LRRC75A antisense RNA 1.

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