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Regulatory network analysis of microRNAs and genes in imatinib-resistant chronic myeloid leukemia

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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.

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Abbreviations

miRNA:

MicroRNA

TFs:

Transcription factors

IM:

Imatinib mesylate

CML:

Chronic myeloid leukemia

NCBI:

National Center for Biotechnology Information

TFBSs:

Transcription factor binding sites

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Authors and Affiliations

  1. Molecular and Cellular Hematology Laboratory, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis, Tunisia

    Ismael Soltani, Hanen Gharbi, Islem Ben Hassine, Ghada Bouguerra, Kais Douzi, Mouheb Teber, Salem Abbes & Samia Menif

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  1. Ismael Soltani
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  2. Hanen Gharbi
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  3. Islem Ben Hassine
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Correspondence to Ismael Soltani.

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This article forms part of a special issue of Functional & Integrative Genomics entitled “miRNA in model and complex organisms” (Issue Editors: Hikmet Budak and Baohong Zhang).

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Soltani, I., Gharbi, H., Hassine, I.B. et al. Regulatory network analysis of microRNAs and genes in imatinib-resistant chronic myeloid leukemia. Funct Integr Genomics 17, 263–277 (2017). https://doi.org/10.1007/s10142-016-0520-1

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