title: Regulatory network analysis of microRNAs and genes in imatinib-resistant chronic myeloid leukemia.
abstract: Targeted therapy in the form of selective breakpoint cluster region-abelson (BCR/ABL) tyrosine kinase inhibitor (imatinib mesylate) has successfully been introduced in the treatment of the chronic myeloid leukemia (CML). However, acquired resistance against imatinib mesylate (IM) has been reported in nearly half of patients and has been recognized as major issue in clinical practice. Multiple resistance genes and microRNAs (miRNAs) are thought to be involved in the IM resistance process. These resistance genes and miRNAs tend to interact with each other through a regulatory network. Therefore, it is crucial to study the impact of these interactions in the IM resistance process. The present study focused on miRNA and gene network analysis in order to elucidate the role of interacting elements and to understand their functional contribution in therapeutic failure. Unlike previous studies which were centered only on genes or miRNAs, the prime focus of the present study was on relationships. To this end, three regulatory networks including differentially expressed, related, and global networks were constructed and analyzed in search of similarities and differences. Regulatory associations between miRNAs and their target genes, transcription factors and miRNAs, as well as miRNAs and their host genes were also macroscopically investigated. Certain key pathways in the three networks, especially in the differentially expressed network, were featured. The differentially expressed network emerged as a fault map of IM-resistant CML. Theoretically, the IM resistance process could be prevented by correcting the included errors. The present network-based approach to study resistance miRNAs and genes might help in understanding the molecular mechanisms of IM resistance in CML as well as in the improvement of CML therapy.
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia. soltaniismael@yahoo.fr.
authors.forename: Ismael
authors.initials: I
authors.lastname: Soltani
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Hanen
authors.initials: H
authors.lastname: Gharbi
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Islem Ben
authors.initials: IB
authors.lastname: Hassine
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Ghada
authors.initials: G
authors.lastname: Bouguerra
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Kais
authors.initials: K
authors.lastname: Douzi
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Mouheb
authors.initials: M
authors.lastname: Teber
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Salem
authors.initials: S
authors.lastname: Abbes
authors.affiliation: Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia.
authors.forename: Samia
authors.initials: S
authors.lastname: Menif
mesh_terms: D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D035683:MicroRNAs / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D000068877:Imatinib Mesylate
keywords: Chronic myeloid leukemia; Imatinib mesylate; MicroRNA; Network; Resistance; Transcription factor