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. 2019 Feb:40:240-250.
doi: 10.1016/j.ebiom.2019.01.022. Epub 2019 Jan 17.

Incorporation of long non-coding RNA expression profile in the 2017 ELN risk classification can improve prognostic prediction of acute myeloid leukemia patients

Cheng-Hong Tsai  1 , Chi-Yuan Yao  2 , Feng-Min Tien  3 , Jih-Luh Tang  4 , Yuan-Yeh Kuo  5 , Yu-Chiao Chiu  6 , Chien-Chin Lin  7 , Mei-Hsuan Tseng  2 , Yen-Ling Peng  2 , Ming-Chih Liu  8 , Chia-Wen Liu  8 , Ming Yao  2 , Liang-In Lin  9 , Wen-Chien Chou  10 , Chien-Yu Chen  11 , Hsin-An Hou  12 , Hwei-Fang Tien  13
Affiliations

Incorporation of long non-coding RNA expression profile in the 2017 ELN risk classification can improve prognostic prediction of acute myeloid leukemia patients

Cheng-Hong Tsai et al. EBioMedicine. 2019 Feb.

Abstract

Background: Expression of long non-coding RNAs (lncRNAs) has recently been recognized as a potential prognostic marker in acute myeloid leukemia (AML). However, it remains unclear whether incorporation of the lncRNAs expression in the 2017 European LeukemiaNet (ELN) risk classification can further improve the prognostic prediction.

Methods: We enrolled 275 newly diagnosed non-M3 AML patients and randomly assigned them to the training (n = 183) and validation cohorts (n = 92). In the training cohort, we formulated a prognostic lncRNA scoring system composed of five lncRNAs with significant prognostic impact from the lncRNA expression profiling.

Findings: Higher lncRNA scores were significantly associated with older age and adverse gene mutations. Further, the higher-score patients had shorter overall and disease-free survival than lower-score patients, which were also confirmed in both internal and external validation cohorts (TCGA database). The multivariate analyses revealed the lncRNA score was an independent prognosticator in AML, irrespective of the risk based on the 2017 ELN classification. Moreover, in the 2017 ELN intermediate-risk subgroup, lncRNA scoring system could well dichotomize the patients into two groups with distinct prognosis. Within the ELN intermediate-risk subgroup, we found that allogeneic hematopoietic stem cell transplantation could provide better outcome on patients with higher lncRNA scores. Through bioinformatics approach, we identified high lncRNA scores were correlated with leukemia/hematopoietic stem cell signatures.

Interpretation: Incorporation of lncRNA scoring system in 2017 ELN classification can improve risk-stratification of AML patients and help clinical decision-making. FUND: This work was supported Ministry of Science and Technology, and Ministry of Health and Welfare of Taiwan.

Keywords: AML; Prognostication; Risk stratification; lncRNA.

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Figures

Fig. 1
Fig. 1
The Kaplan-Meier survival curves for OS (A) and DFS (B) of AML patients stratified by lncRNA scores. The prognostic impact of the lncRNA scoring system could be validated in an independent internal cohort (C)(D), and the external cohort (E). Patients with normal cytogenetics could also be divided by lncRNA scores into two groups with distinct outcomes (F)(G).
Fig. 1
Fig. 1
The Kaplan-Meier survival curves for OS (A) and DFS (B) of AML patients stratified by lncRNA scores. The prognostic impact of the lncRNA scoring system could be validated in an independent internal cohort (C)(D), and the external cohort (E). Patients with normal cytogenetics could also be divided by lncRNA scores into two groups with distinct outcomes (F)(G).
Fig. 2
Fig. 2
The patients with MRC intermediate-risk cytogenetics could be well risk-stratified by lncRNA scoring system (A) (B). For the 2017 ELN intermediate-risk patients, the lncRNA score still served as a good prognosticator (C)(D).
Fig. 3
Fig. 3
Comparison of the genome-wide RNA expressions between the patients with higher and lower lncRNA scores. (A) The x-axis specifies the fold-changes (FC) and the y-axis specifies the negative logarithm to the base 10 of the t-test P values. The vertical and horizontal lines reflect the filtering criteria (FC = ±1.5 and P value = .0001). Red and green dots represented probe sets for transcripts expressed at significantly higher (n = 174) or lower (n = 421) levels in high-score patients, respectively. (B) Heatmap of the selected differential expressed genes. (C) GSEA confirmed that leukemia or hematopoietic stem cell signature containing genesets were enriched in higher lncRNA score patients. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Comparison of the genome-wide RNA expressions between the patients with higher and lower lncRNA scores. (A) The x-axis specifies the fold-changes (FC) and the y-axis specifies the negative logarithm to the base 10 of the t-test P values. The vertical and horizontal lines reflect the filtering criteria (FC = ±1.5 and P value = .0001). Red and green dots represented probe sets for transcripts expressed at significantly higher (n = 174) or lower (n = 421) levels in high-score patients, respectively. (B) Heatmap of the selected differential expressed genes. (C) GSEA confirmed that leukemia or hematopoietic stem cell signature containing genesets were enriched in higher lncRNA score patients. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
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