title: Modulating the Growth and Imatinib Sensitivity of Chronic Myeloid Leukemia Stem/Progenitor Cells with Pullulan/MicroRNA Nanoparticles In Vitro.
abstract: Chronic myeloid leukemia (CML) originates from normal hematopoietic stem cells acquiring Philadelphia chromosome (Ph) to generate BCR-ABL fusion gene whose protein product has deregulated tyrosine kinase activity. Specific inhibitors against BCR-ABL, such as Imatinib mesylate (IM), have greatly improved CML management; however, no single agent is a cure yet. Delivery of microRNA (miRNA) using non-viral vectors has been utilized to inhibit various cancer cells; however, the efficacy of this approach to target CML stem/progenitor cells has not been elucidated. In this study, we firstly validated that spermine-introduced pullulan (Ps) was a robust non-viral vector for delivery of miRNA to CML cells, including the CD34+ cells from clinical isolates. We then found that the miR-181a/RALA (V-ral simian leukemia viral oncogene homolog A) axis was aberrantly expressed in the CML CD34+ cells. The delivery of miR-181a specifically inhibited the growth of CML CD34+ cells, possibly via the inhibition of RALA. In contrast, miR-181a did not evidently affect the normal hematopoietic CD34+ cells. In addition, miR-181a increased IM sensitivity of the CD34+ CML cells. Taken together, we have therefore demonstrated that the delivery of miR-181a using Ps to CML stem/progenitor cells leads to their growth inhibition and enhancement of IM sensitivity, which will possibly be beneficial to CML treatment.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Ma
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Jundan
authors.initials: J
authors.lastname: Xie
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Zhang
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhou
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.forename: Dawei
authors.initials: D
authors.lastname: Guo
authors.forename: Lingying
authors.initials: L
authors.lastname: Zhu
authors.forename: Lun
authors.initials: L
authors.lastname: Xiao
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.forename: Suning
authors.initials: S
authors.lastname: Chen
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005936:Glucans / Q000737:chemistry; D006801:Humans; D000068877:Imatinib Mesylate / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology*; D008875:Middle Aged; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry*; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D014162:Transfection; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D005936:Glucans; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D000068877:Imatinib Mesylate; C009109:pullulan