A Systematic Review of Candidate miRNAs, Its Targeted Genes and Pathways in Chronic Myeloid Leukemia-An Integrated Bioinformatical Analysis

Abstract

Chronic myeloid leukaemia is blood cancer due to a reciprocal translocation, resulting in a BCR-ABL1 oncogene. Although tyrosine kinase inhibitors have been successfully used to treat CML, there are still cases of resistance. The resistance occurred mainly due to the mutation in the tyrosine kinase domain of the BCR-ABL1 gene. However, there are still many cases with unknown causes of resistance as the etiopathology of CML are not fully understood. Thus, it is crucial to figure out the complete pathogenesis of CML, and miRNA can be one of the essential pathogeneses. The objective of this study was to systematically review the literature on miRNAs that were differentially expressed in CML cases. Their target genes and downstream genes were also explored. An electronic search was performed via PubMed, Scopus, EBSCOhost MEDLINE, and Science Direct. The following MeSH (Medical Subject Heading) terms were used: chronic myeloid leukaemia, genes and microRNAs in the title or abstract. From 806 studies retrieved from the search, only clinical studies with in-vitro experimental evidence on the target genes of the studied miRNAs in CML cells were included. Two independent reviewers independently scrutinised the titles and abstracts before examining the eligibility of studies that met the inclusion criteria. Study design, sample size, sampling type, and the molecular method used were identified for each study. The pooled miRNAs were analysed using DIANA tools, and target genes were analysed with DAVID, STRING and Cytoscape MCODE. Fourteen original research articles on miRNAs in CML were included, 26 validated downstream genes and 187 predicted target genes were analysed and clustered into 7 clusters. Through GO analysis, miRNAs' target genes were localised throughout the cells, including the extracellular region, cytosol, and nucleus. Those genes are involved in various pathways that regulate genomic instability, proliferation, apoptosis, cell cycle, differentiation, and migration of CML cells.

Keywords: BCR-ABL1; chronic myeloid leukemia; genes; microRNA; pathways.

Figure 1

PRISMA flow diagram for studies selection in this systematic review.

Figure 2

PPI network and modular analysis of downstream genes. From STRING online database analysis, a total of 26 proteins were filtered into a PPI network complex. The green nodes represent a functional annotation cluster that was identified from Cytoscape MCODE. This functional annotation clustering showed a cluster consisted of 12 proteins.

Figure 3

PPI network and modular analysis of downstream genes. From STRING online database analysis, a total of 187 proteins were filtered into a PPI network complex with 136 nodes and 211 edges. Six clusters were identified from Cytoscape MCODE.

Figure 4

Summary of the bioinformatical analysis findings.