Integrating microRNA and mRNA expression in rapamycin-treated T-cell acute lymphoblastic leukemia

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) has a relatively improved remission rate, but the poor outcomes are primarily due to resistance and relapse. Moreover, organs infiltration trends to occur during remission. Rapamycin was applied to treat malignancies for decades. In this investigation, we aimed to explore the molecular mechanisms and pathway changes during the T-ALL therapeutic process. T-ALL cell line Molt-4 cells were treated with rapamycin and performed microarray analysis to identify the deregulated miRNAs and mRNAs (log2 fold change>2 or <-2). To obtain regulatory miRNA/mRNA network, miRNA target prediction softwares and Cytoscape were used to plot and modularize the rapamycin treatment-related network. Surprisingly, the enriched pathways were not involved in mediating either cell death or apoptosis but were responsible for angiogenesis, cell survival, and anti-apoptosis, which is consistent with the Gene Ontology analysis and PPI network based on all deregulated mRNAs, indicating that these elements likely play a role in promoting Molt-4 cell survival or escaping from rapamycin. The expression of 3 miRNAs (miR-149-3p, miR-361-3p, and miR-944) and their putative targets, which play central roles in their module, were validated by qRT-PCR. These results provide novel insight into potentially relevant biological pathways for T-ALL cells escaping from chemotherapy or developing central nervous system infiltration.

Keywords: Cell survival pathways; Rapamycin; Regulatory network; T-cell acute lymphoblastic leukemia; miRNA.