Modulating the Growth and Imatinib Sensitivity of Chronic Myeloid Leukemia Stem/Progenitor Cells with Pullulan/MicroRNA Nanoparticles In Vitro.
JOURNAL OF BIOMEDICAL NANOTECHNOLOGY(2015)
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.
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Key words
Chronic Myeloid Leukemia,miR-181a,Spermine-Introduced Pullulan,Stem/Progenitor Cells,Imatinib Mesylate
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