Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment

Oshrat Hershkovitz-Rokah, Shira Modai, Metsada Pasmanik-Chor, Amos Toren, Noam Shomron, Pia Raanani, Ofer Shpilberg, Galit Granot

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

MicroRNAs (miRNAs) are small noncoding RNAs that participate in many biological processes by posttranscriptionally regulating gene expression. Dysregulation of miRNA expression has been shown to be typical of many neoplasms. Chronic myeloid leukemia (CML) is a disorder of hematopoietic stem cells carrying the Philadelphia (Ph) chromosome and an oncogenic BCR-ABL tyrosine kinase fusion gene. While the development of tyrosine kinase inhibitors (TKIs) like imatinib has revolutionized treatment of CML, it has become increasingly clear in recent years that TKI treatment alone will not be curative in many cases. Thus, further dissection of the regulatory networks that drive BCR-ABL-induced malignant transformation may help to identify other novel therapeutic approaches that complement TKI treatment. In this study we demonstrate that the expression of miR-424 is markedly low in CML cell lines and patient samples at time of diagnosis. With the aid of bioinformatics analysis we revealed a conserved target site for miR-424 in the 3'-untranslated region (UTR) of the ABL gene. Via luciferase assays, we showed that miR-424 directly targets BCR-ABL. Overexpression of miR-424 was shown to suppress proliferation and induce apoptosis of K562 cells as well as sensitize these cells to imatinib treatment. These findings strongly suggest that miR-424 acts as a tumor suppressor by downregulating BCR-ABL expression. Up-regulation of miR-424 in CML cells may therefore have a therapeutic effect against this disease.

Original languageEnglish
Pages (from-to)245-256
Number of pages12
JournalCancer Letters
Volume360
Issue number2
DOIs
StatePublished - 1 May 2015

Keywords

  • Apoptosis
  • BCR-ABL
  • CML
  • Imatinib
  • MiR-424

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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