1. Silencing of miR-21 sensitizes CML CD34+ stem/progenitor cells to imatinib-induced apoptosis by blocking PI3K/AKT pathway.
- Author
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Wang WZ, Pu QH, Lin XH, Liu MY, Wu LR, Wu QQ, Chen YH, Liao FF, Zhu JY, and Jin XB
- Subjects
- Adult, Antigens, CD34 immunology, Child, Female, Gene Silencing, Humans, Imatinib Mesylate pharmacology, Infant, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Male, Middle Aged, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Real-Time Polymerase Chain Reaction, Transfection, Young Adult, Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis physiology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, MicroRNAs antagonists & inhibitors, Neoplastic Stem Cells drug effects, Signal Transduction physiology
- Abstract
BCR-ABL tyrosine kinase inhibitor imatinib fails to eradicate leukemia stem cells (LSCs), the underlying mechanisms maintaining CML LSCs remain poorly understood. Here, we showed that transient inhibition of miR-21 by antagomiR-21 markedly increased imatinib-induced apoptosis in CML, but not normal CD34+ stem/progenitor cells. Furthermore, PI3K inhibitors also significantly sensitized CML CD34+ cells to imatinib-induced apoptosis. MiR-21 or PI3K inhibitor in combination with imatinib treatment significantly decreased AKT phosphorylation and c-Myc expression than either agent did alone, but did not affect Bim and Bcl-6 expresssion. These findings indicate that miR-21 is required for maintaining the imatinib-resistant phenotype of CML CD34+ cells through PI3K/AKT signaling pathway, thus providing the basis for a promising therapeutic approach to eliminate CML LSCs., (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Published
- 2015
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