Abstract
BackgroundLong noncoding RNAs (lncRNA) play a role in leukemogenesis, maintenance, development, and therapeutic resistance of AML. While few studies have focused on the prognostic significance of LINC00649 in AML, which we aim to investigate in this present study.MethodsWe compared the expression level of LINC00649 between AML patients and healthy controls. The Kaplan-Meier curves of AML patients expressing high versus low level of LINC00649 was performed. The LINC00649 correlated genes/miRNAs/lncRNAs and methylation CpG sites were screened by Pearson correlation analysis with R (version 3.6.0), using TCGA-LAML database. The LINC00649 associated ceRNA network was established using lncBase 2.0 and miRWalk 2.0 online tools, combining results from correlation analysis. Finally, a prediction model was constructed using LASSO-Cox regression.ResultsLINC00649 was underexpressed in bone marrow of AML group than that in healthy control group. The patients of LINC00649-low group have significantly inferior PFS and OS. A total of 154 mRNAs, 31 miRNAs, 28 lncRNAs and 1590 methylated CpG sites were identified to be significantly correlated with LINC00649. Furthermore, the network of ceRNA was established with 6 miRNAs and 122 mRNAs. The Lasso-Cox model fitted OS/PFS to novel prediction models, which integrated clinical factors, ELN risk stratification, mRNA/miRNA expression and methylation profiles. The analysis of time-dependent ROC for our model showed a superior AUC (AUC = 0.916 at 1 year, AUC = 0.916 at 3 years, and AUC = 0.891 at 5 years).ConclusionsLow expression of LINC00649 is a potential unfavorable prognostic marker for AML patients, which requires the further validation. The analysis by LASSO-COX regression identified a novel comprehensive model with a superior diagnostic utility, which integrated clinical and genetic variables.
Highlights
Long noncoding RNAs play a role in leukemogenesis, maintenance, development, and therapeutic resistance of Acute myeloid leukemia (AML)
HOX Transcription Antisense RNA (HOTAIR) exerts a prooncogenic effect in AML, which suppresses p15 expression by methylation of p15 promoter mediated by PRC2, and increases of HOXA5 methylation by directly recruiting DNMT3B [5, 6]
Establishment of prediction model for AML survival In above analysis, we identified the LINC00649-centric competitive endogenous RNA (ceRNA) network and methylation changes in relevance of LINC00649, which were supposed to be key elements linking to prognosis of AML
Summary
Long noncoding RNAs (lncRNA) play a role in leukemogenesis, maintenance, development, and therapeutic resistance of AML. The size of long noncoding RNAs are generally longer than two hundred nucleotides, and do not have the potential of protein-coding. The HOTAIRM1 is another wellstudied lncRNA in AML, which played a potential oncogenic role by enhancing expression of HOXA1–4 genes [7]. These results suggest HOXA family genes are important targets of AML-related lncRNAs. HOXA family included 11 genes (HOXA1–7, HOXA9–11 and HOXA13), encoding conserve transcription factors in relation with normal hematopoiesis [8,9,10]. While dysregulated expression of HOXA family genes is associated with oncogenesis [11]
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