Revealing key lncRNAs in cytogenetically normal acute myeloid leukemia by reconstruction of the lncRNA–miRNA–mRNA network

Abstract

Cytogenetically normal acute myeloid leukemia (CN-AML) is a heterogeneous disease with different prognoses. Researches on prognostic biomarkers and therapy targets of CN-AML are still ongoing. Instead of protein-coding genes, more and more researches were focused on the non-coding RNAs especially long non-coding RNAs (lncRNAs) which may play an important role in the development of AML. Although a large number of lncRNAs have been found, our knowledge of their functions and pathological process is still in its infancy. The purpose of this research is to identify the key lncRNAs and explore their functions in CN-AML by reconstructing the lncRNA–miRNA–mRNA network based on the competitive endogenous RNA (ceRNA) theory. We reconstructed a global triple network based on the ceRNA theory using the data from National Center for Biotechnology Information Gene Expression Omnibus and published literature. According to the topological algorithm, we identified the key lncRNAs which had both the higher node degrees and the higher numbers of lncRNA–miRNA pairs and total pairs in the ceRNA network. Meanwhile, Gene Ontology (GO) and pathway analysis were performed using databases such as DAVID, KOBAS and Cytoscape plug-in ClueGO respectively. The lncRNA–miRNA–mRNA network was composed of 90 lncRNAs,33mRNAs,26 miRNAs and 259 edges in the lncRNA upregulated group, and 18 lncRNAs,11 mRNAs,6 miRNAs and 45 edges in the lncRNA downregulated group. The functional assay showed that 53 pathways and 108 GO terms were enriched. Three lncRNAs (XIST, TUG1, GABPB1-AS1) could possibly be selected as key lncRNAs which may play an important role in the development of CN-AML. Particularly, GABPB1-AS1 was highly expressed in CN-AML by both bioinformatic analysis and experimental verification in AML cell line (THP-1) with quantitative real‐time polymerase chain reaction. In addition, GABPB1-AS1 was also negatively correlated with overall survival of AML patients. The lncRNA–miRNA–mRNA network revealed key lncRNAs and their functions in CN-AML. Particularly, lncRNA GABPB1-AS1 was firstly proposed in AML. We believe that GABPB1-AS1 is expected to become a candidate prognostic biomarker or a potential therapeutic target.

Identification of lncRNA–miRNA–mRNA networks in circulating exosomes as potential biomarkers for systemic sclerosis

“…ENST00000313807 ( P < 0.0001), and NON-HSAT194388.1 ( P = 0.0001) were positively correlated with COL1A1 , and hsa-miR-29a-3p was negatively correlated with COL1A1 ( P < 0.01). lncRNAs involved in the ceRNA mechanism are positively correlated with mRNAs, while lncRNAs and mRNAs are negatively correlated with miRNAs ( 10 , 36 ). The relationships of ENST00000313807-hsa-miR-29a-3p- COL1A1 and NON-HSAT194388.1-hsa-miR-29a-3p- COL1A1 conformed to the ceRNA mechanism.…”

Naringenin induces the cell apoptosis of acute myeloid leukemia cells by regulating the lncRNA XIST/miR-34a/HDAC1 signaling

“…In addition, XIST can interact with mRNA competitively by adsorbing miRNAs [ 42 ]. The important role of XIST in leukemia has been verified in cytogenetically normal AML by constructing a network of lncRNA-miRNA-mRNA [ 9 ]. Many important signaling pathways, such as PI3K/AKT signaling, forkhead box O signaling, p53 signaling, and Ras signaling, have been shown to be associated with XIST [ 9 ].…”

“…The important role of XIST in leukemia has been verified in cytogenetically normal AML by constructing a network of lncRNA-miRNA-mRNA [ 9 ]. Many important signaling pathways, such as PI3K/AKT signaling, forkhead box O signaling, p53 signaling, and Ras signaling, have been shown to be associated with XIST [ 9 ]. Consistently, the present study found that the expression of XIST was increased in HL60 cells.…”

“…Another study indicates that USP30-AS1 may enhance the survival of AML cells by cis -regulating the expression of USP30 and ankyrin repeat domain 13A [ 8 ]. In the study of lncRNA-microRNA (miR)-NA-mRNA network in cytogenetically normal AML, three lncRNAs, including X inactive specific transcript (XIST), taurine upregulated 1, and GABPB1 antisense RNA 1, are found to have higher node degrees and higher numbers of lncRNA-miRNA pairs and total pairs [ 9 ]. XIST expression in AML KG-1 cells is increased, and the increase is associated with drug resistance through the sponging of miR-29a expression and an increase of MYC proto-oncogene, basic helix-loop-helix (bHLH) transcription factor proto-oncogene, and bHLH transcription factor MYC expression [ 10 ].…”

Long non-coding RNAs: emerging functional players in the pathobiology and progression of myeloid leukemia

“…The number of lncRNAs listed in the microRNA sponging group has increased in recent times, as sponging is one of the common mechanisms of gene regulation (Sun et al, 2022). For example, the lncRNA H19 that is otherwise known for its epigenetic regulation acts as a sponge for miR-326, miR-19a-3p, and miR-29a-3p in the hematopoiesis and AML context (Zhao et al, 2017;Zhao and Liu, 2019;Mofidi et al, 2021).…”