Integrative computational in-depth analysis of dysregulated miRNA-mRNA interactions in drug-resistant pediatric acute lymphoblastic leukemia cells: an attempt to obtain new potential gene-miRNA pathways involved in response to treatment
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Acute lymphoblastic leukemia (ALL) is the major neoplasia type among children. Despite the tremendous success of current treatment strategies, drug resistance still remains a major cause of chemotherapy failure and relapse in pediatric patients. Overwhelming evidence illustrates that microRNAs (miRNAs) act as post-transcriptional regulators of drug-resistance-related genes. The current study was aimed at how dysregulated miRNA-mRNA-signaling pathway interaction networks mediate resistance to four commonly used chemotherapy agents in pediatric ALL, including asparaginase, daunorubicin, prednisolone, and vincristine. Using public expression microarray datasets, a holistic in silico approach was utilized to investigate candidate drug resistance miRNA-mRNA-signaling pathway interaction networks in pediatric ALL. Our systems biology approach nominated significant drug resistance and cross-resistance miRNAs, mRNAs, and cell signaling pathways based on anti-correlative relationship between miRNA and mRNA expression pattern. To sum up, our systemic analysis disclosed either a new potential role of miRNAs, or a possible mechanism of cellular drug resistance, in chemotherapy resistance of pediatric ALL. The current study may shed light on predicting drug response and overcoming drug resistance in childhood ALL for subsequent generations of chemotherapies.
KeywordsAcute lymphoblastic leukemia Drug resistance miRNA Signaling pathway Therapeutic targets
Acute lymphoblastic leukemia
Database for Annotation, Visualization and Integrated Discovery
Gene Expression Omnibus
Standard error of the mean
T cell receptor
11-β-Hydroxysteroid dehydrogenase 2
We are grateful to Drs. Mohammad Dabaghi (Jena University Hospital, Jena, Germany), Marjan Abedi (University of Isfahan, Isfahan, Iran), and Mansureh Entezar-e-ghaem (University of Isfahan, Isfahan, Iran) for their kind consultations.
Compliance with ethical standards
The authors have no financial relationships relevant to this article to disclose.
Conflicts of interest
Authorship and disclosures
Hamzeh Mesrian Tanha: The study conception and design, data collection and analysis, interpretation, and manuscript writing.
Marjan Mojtabavi Naeini: Data collection and analysis, interpretation, and manuscript writing.
Soheila Rahgozar: Conception, manuscript writing, and final approval of manuscript.
Alireza Moafi: Conception and final approval of manuscript.
Mohammad Amin Honardoost: Data analysis.
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