title: Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia.
abstract: Current treatments for acute myeloid leukemia (AML) are designed to target rapidly dividing blast populations with limited success in eradicating the functionally distinct leukemia stem cell (LSC) population, which is postulated to be responsible for disease resistance and relapse. We have previously reported high miR-126 expression levels to be associated with a LSC-gene expression profile. Therefore, we hypothesized that miR-126 contributes to 'stemness' and is a viable target for eliminating the LSC in AML. Here we first validate the clinical relevance of miR-126 expression in AML by showing that higher expression of this microRNA (miR) is associated with worse outcome in a large cohort of older (⩾60 years) cytogenetically normal AML patients treated with conventional chemotherapy. We then show that miR-126 overexpression characterizes AML LSC-enriched cell subpopulations and contributes to LSC long-term maintenance and self-renewal. Finally, we demonstrate the feasibility of therapeutic targeting of miR-126 in LSCs with novel targeting nanoparticles containing antagomiR-126 resulting in in vivo reduction of LSCs likely by depletion of the quiescent cell subpopulation. Our findings suggest that by targeting a single miR, that is, miR-126, it is possible to interfere with LSC activity, thereby opening potentially novel therapeutic approaches to treat AML patients.
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Dorrance
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: P
authors.initials: P
authors.lastname: Neviani
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: G J
authors.initials: GJ
authors.lastname: Ferenchak
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: D
authors.initials: D
authors.lastname: Nicolet
authors.affiliation: Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors.forename: K S
authors.initials: KS
authors.lastname: Maharry
authors.affiliation: Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA.
authors.forename: H G
authors.initials: HG
authors.lastname: Ozer
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hoellarbauer
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Khalife
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Hill
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Yadav
authors.affiliation: Comparative Pathology and Mouse Phenotyping Shared Resource, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: B N
authors.initials: BN
authors.lastname: Bolon
authors.affiliation: Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Department of Biomedical Informatics, Ohio State University, Columbus, OH, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Lee
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Garzon
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.|Comprehensive Cancer Center, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000818:Animals; D019175:DNA Methylation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000401:mortality / Q000628:therapy*; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000502:physiology; D053758:Nanoparticles / Q000008:administration & dosage*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000502:physiology*
chemical_list: C527111:MIRN126 microRNA, human; D035683:MicroRNAs; D017493:Leukocyte Common Antigens