title: Silencing of miR-21 sensitizes CML CD34+ stem/progenitor cells to imatinib-induced apoptosis by blocking PI3K/AKT pathway.
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.
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Wei-Zhang
authors.initials: WZ
authors.lastname: Wang
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Qiao-Hong
authors.initials: QH
authors.lastname: Pu
authors.affiliation: Department of clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
authors.forename: Xiang-Hua
authors.initials: XH
authors.lastname: Lin
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China.
authors.forename: Man-Yu
authors.initials: MY
authors.lastname: Liu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Wu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Wu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Yong-Heng
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China; Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, People's Republic of China.
authors.forename: Fen-Fang
authors.initials: FF
authors.lastname: Liao
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China.
authors.forename: Jia-Yong
authors.initials: JY
authors.lastname: Zhu
authors.affiliation: Guangdong Province Key Laboratory of Pharmaceutical Bioactive Substances, Guangzhou, People's Republic of China. Electronic address: jinxf2001@163.com.
authors.forename: Xiao-Bao
authors.initials: XB
authors.lastname: Jin
mesh_terms: D000328:Adult; D018952:Antigens, CD34 / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002648:Child; D005260:Female; D020868:Gene Silencing; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007223:Infant; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D000970:Antineoplastic Agents; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D051057:Proto-Oncogene Proteins c-akt
keywords: Apoptosis; CD34(+) stem/progenitor cells; CML; Imatinib; MiR-21