Identifying and validating a combined mRNA and MicroRNA signature in response to imatinib treatment in a chronic myeloid leukemia cell line

Steven Bhutra, Divya Lenkala, Bonnie LaCroix, Meng Ye, R. Stephanie Huang

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Imatinib, a targeted tyrosine kinase inhibitor, is the gold standard for managing chronic myeloid leukemia (CML). Despite its wide application, imatinib resistance occurs in 20-30% of individuals with CML. Multiple potential biomarkers have been identified to predict imatinib response; however, the majority of them remain externally uncorroborated. In this study, we set out to systematically identify gene/microRNA (miRNA) whose expression changes are related to imatinib response. Through a Gene Expression Omnibus search, we identified two genome-wide expression datasets that contain expression changes in response to imatinib treatment in a CML cell line (K562): one for mRNA and the other for miRNA. Significantly differentially expressed transcripts/miRNAs post imatinib treatment were identified from both datasets. Three additional filtering criteria were applied 1) miRbase/miRanda predictive algorithm; 2) opposite direction of imatinib effect for genes and miRNAs; and 3) literature support. These criteria narrowed our candidate gene-miRNA to a single pair: IL8 and miR-493-5p. Using PCR we confirmed the significant up-regulation and down-regulation of miR-493-5p and IL8 by imatinib treatment, respectively in K562 cells. In addition, IL8 expression was significantly down-regulated in K562 cells 24 hours after miR-493-5p mimic transfection (p=0.002). Furthermore, we demonstrated significant cellular growth inhibition after IL8 inhibition through either gene silencing or by over-expression of miR-493-5p (p=0.0005 and p=0.001 respectively). The IL8 inhibition also further sensitized K562 cells to imatinib cytotoxicity (p<0.0001). Our study combined expression changes in transcriptome and miRNA after imatinib exposure to identify a potential gene-miRNA pair that is a critical target in imatinib response. Experimental validation supports the relationships between IL8 and miR-493-5p and between this gene-miRNA pair and imatinib sensitivity in a CML cell line. Our data suggests integrative analysis of multiple omic level data may provide new insight into biomarker discovery as well as mechanisms of imatinib resistance.

Original languageEnglish (US)
Article numbere115003
JournalPloS one
Volume9
Issue number12
DOIs
StatePublished - Dec 15 2014

Bibliographical note

Publisher Copyright:
© 2014 Bhutra et al.

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