Downregulation of miR-451 in Tunisian chronic myeloid leukemia patients: potential implication in imatinib resistance.
OBJECTIVE
Resistance to imatinib has been recognized as a major challenge for the treatment of chronic myeloid leukemia (CML). Aberrant expression of miR-451 has been reported to participate in anticancer drug resistance. However, the role of miR-451 in imatinib resistance has not been investigated. The present study was undertaken to determine the expression of miR-451 in order to find a possible association between the expression of this miRNA and imatinib resistance in Tunisian CML patients.


METHODS
First, real-time RT-PCR was performed to identify the expression of miR-451 in peripheral leukocytes of 59 CML patients treated with imatinib. Then, bioinformatics analysis was carried out to understand the regulatory roles of miR-451 in imatinib-resistant process.


RESULTS
Downregulated miR-451 was observed in imatinib-resistant CML cases. In silico analysis identified MYC as a potential target of miR-451. We further revealed the existence of an MYC-binding site in MiR-451 promoter region. On the other hand, increased level of MYC was detected in imatinib-resistant CML cases which may explain the causative role of MYC in CML cases and the downregulation of miR-451.


CONCLUSIONS
Taken together, our findings suggest that miR-451 and MYC form together a regulatory loop which may act as a potential therapeutic target, and disruption of suggested regulatory loop could help to improve CML therapy.
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Ismael
I
Soltani
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Kais
K
Douzi
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Hanen
H
Gharbi
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Islem
I
Benhassine
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Mouheb
M
Teber
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Hassiba
H
Amouri
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Hind
H
Ben Hadj Othman
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Ahlem
A
Farrah
b Aziza Othmana Hospital , Tunis , Tunisia.
Raihane
R
Ben Lakhel
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Salem
S
Abbes
a Molecular and Cellular Hematology Laboratory , Institut Pasteur de Tunis, Université Tunis El Manar , Tunis , Tunisia.
Samia
S
Menif
D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D019295:Computational Biology; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014416:Tunisia
D000970:Antineoplastic Agents; C531201:MIRN451 microRNA, human; C489427:MYC protein, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D000068877:Imatinib Mesylate
Chronic myeloid leukemia; MYC; imatinib mesylate; miR-451; resistance