Micro-RNA response to imatinib mesylate in patients with chronic myeloid leukemia.
BACKGROUND
Micro-RNAs (miRNAs) control gene expression by destabilizing targeted transcripts and inhibiting their translation. Aberrant expression of miRNAs has been described in many human cancers, including chronic myeloid leukemia. Current first-line therapy for newly diagnosed chronic myeloid leukemia is imatinib mesylate, which typically produces a rapid hematologic response. However the effect of imatinib on miRNA expression in vivo has not been thoroughly examined.


METHODS
Using a TaqMan Low-Density Array system, we analyzed miRNA expression in blood samples from newly diagnosed chronic myeloid leukemia patients before and within the first two weeks of imatinib therapy. Quantitative real-time PCR was used to validate imatinib-modulated miRNAs in sequential primary chronic myeloid leukemia samples (n=11, plus 12 additional validation patients). Bioinformatic target gene prediction analysis was performed based on changes in miRNA expression.


RESULTS
We observed increased expression of miR-150 and miR-146a, and reduced expression of miR-142-3p and miR-199b-5p (3-fold median change) after two weeks of imatinib therapy. A significant correlation (P<0.05) between the Sokal score and pre-treatment miR-142-3p levels was noted. Expression changes in the same miRNAs were consistently found in an additional cohort of chronic myeloid leukemia patients, as compared to healthy subjects. Peripheral blood cells from chronic phase and blast crisis patients displayed a 30-fold lower expression of miR-150 compared to normal samples, which is of particular interest since c-Myb, a known target of miR-150, was recently shown to be necessary for Bcr-Abl-mediated transformation.


CONCLUSIONS
We found that imatinib treatment of chronic myeloid leukemia patients rapidly normalizes the characteristic miRNA expression profile, suggesting that miRNAs may serve as a novel clinically useful biomarker in this disease.
Flamant
Stéphane
S
Gene and Stem Cell Therapy Program, Centenary Institute, Locked Bag No 6, Newtown, NSW 2042, Australia.
Ritchie
William
W
Guilhot
Joëlle
J
Holst
Jeff
J
Bonnet
Marie-Laure
ML
Chomel
Jean-Claude
JC
Guilhot
François
F
Turhan
Ali G
AG
Rasko
John E J
JE
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D000970:Antineoplastic Agents; D001549:Benzamides; D000068877:Imatinib Mesylate; D035683:MicroRNAs; D010879:Piperazines; D011743:Pyrimidines; C533097:MIR150, human
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