title: Restoration of miR-424 suppresses BCR-ABL activity and sensitizes CML cells to imatinib treatment.
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.
authors.affiliation: Felsenstein Medical Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Oshrat
authors.initials: O
authors.lastname: Hershkovitz-Rokah
authors.affiliation: Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Shira
authors.initials: S
authors.lastname: Modai
authors.affiliation: Bioinformatics Unit, Faculty of Life Sciences, Tel Aviv University, Israel.
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.affiliation: Department of Pediatric Hematology-Oncology, Safra Children's Hospital, Tel-Hashomer, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Toren
authors.affiliation: Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.affiliation: Felsenstein Medical Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Israel; Institute of Hematology, Davidoff Cancer Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Israel.
authors.forename: Pia
authors.initials: P
authors.lastname: Raanani
authors.affiliation: Institute of Hematology, Assuta Medical Center, Tel-Aviv, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Shpilberg
authors.affiliation: Felsenstein Medical Research Center, Beilinson Hospital, Sackler School of Medicine, Tel Aviv University, Israel. Electronic address: galitg@clalit.org.il.
authors.forename: Galit
authors.initials: G
authors.lastname: Granot
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001483:Base Sequence; D001549:Benzamides / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D003131:Combined Modality Therapy; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D035683:MicroRNAs / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C554214:MIRN424 microrna, human; D035683:MicroRNAs; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl
keywords: Apoptosis; BCR–ABL; CML; Imatinib; miR-424