title: Pharmacological targeting of miR-155 via the NEDD8-activating enzyme inhibitor MLN4924 (Pevonedistat) in FLT3-ITD acute myeloid leukemia.
abstract: High levels of microRNA-155 (miR-155) are associated with poor outcome in acute myeloid leukemia (AML). In AML, miR-155 is regulated by NF-κB, the activity of which is, in part, controlled by the NEDD8-dependent ubiquitin ligases. We demonstrate that MLN4924, an inhibitor of NEDD8-activating enzyme presently being evaluated in clinical trials, decreases binding of NF-κB to the miR-155 promoter and downregulates miR-155 in AML cells. This results in the upregulation of the miR-155 targets SHIP1, an inhibitor of the PI3K/Akt pathway, and PU.1, a transcription factor important for myeloid differentiation, leading to monocytic differentiation and apoptosis. Consistent with these results, overexpression of miR-155 diminishes MLN4924-induced antileukemic effects. In vivo, MLN4924 reduces miR-155 expression and prolongs the survival of mice engrafted with leukemic cells. Our study demonstrates the potential of miR-155 as a novel therapeutic target in AML via pharmacologic interference with NF-κB-dependent regulatory mechanisms. We show the targeting of this oncogenic microRNA with MLN4924, a compound presently being evaluated in clinical trials in AML. As high miR-155 levels have been consistently associated with aggressive clinical phenotypes, our work opens new avenues for microRNA-targeting therapeutic approaches to leukemia and cancer patients.
authors.affiliation: Program of Molecular, Cellular, and Developmental Biology, The Ohio State University, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Khalife
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Radomska
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Santhanam
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: P
authors.initials: P
authors.lastname: Neviani
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Saultz
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Wu
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Alachkar
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Anghelina
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Dorrance
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Curfman
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Bloomfield
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Medeiros
authors.affiliation: Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: D
authors.initials: D
authors.lastname: Perrotti
authors.affiliation: William G. Lowrie Department of Chemical and Biomolecular Engineering, The Ohio State University, Columbus, OH, USA.|Nanoscale Science and Engineering Center for Affordable Nanoengineering of Polymeric Biomedical Devices, The Ohio State University, Columbus, OH, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Lee
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.|Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Lee
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: F
authors.initials: F
authors.lastname: Pichiorri
authors.affiliation: Department of Molecular Virology, Immunology and Cancer Genetics, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Garzon
authors.affiliation: Division of Hematology & Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Guzman
authors.affiliation: James P. Wilmot Cancer Center and Department of Medicine, University of Rochester, Rochester, NY, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Mendler
authors.affiliation: Division of Hematopoietic Stem Cell & Leukemia Research, Department of Hematology & HCT, Gehr Family Center for Leukemia, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D047369:Chromatin Immunoprecipitation; D003517:Cyclopentanes / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014407:Tumor Cells, Cultured; D014452:Ubiquitins / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D003517:Cyclopentanes; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D011743:Pyrimidines; D012333:RNA, Messenger; D014452:Ubiquitins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C539933:pevonedistat