title: Effects of miRNA-15 and miRNA-16 expression replacement in chronic lymphocytic leukemia: implication for therapy.
abstract: Chronic lymphocytic leukemia (CLL) clones are characterized by loss of a critical region in 13q14.3, (del(13)(q14)) involving the microRNA (miRNA) cluster miR-15a and miR-16-1. We have investigated the effects of replacement of miR-15a and miR-16-1. CLL cells transfected with these miRNA mimics exhibited a decrease in cell viability in vitro and impaired capacity for engraftment and growth in NOD/Shi-scid,γcnull (NSG) mice. No synergistic effects were observed when the two miRNA mimics were combined. The phenomena were not restricted to CLL with the del(13)(q14) lesion. Similar effects induced by miRNA mimics were seen in cells with additional chromosomal abnormalities with the exception of certain CLL clones harboring TP53 alterations. Administration of miRNA mimics to NSG mice previously engrafted with CLL clones resulted in substantial tumor regression. CLL cell transfection with miR-15a and miR-16-1-specific inhibitors resulted in increased cell viability in vitro and in an enhanced capacity of the engrafted cells to grow in NSG mice generating larger splenic nodules. These data demonstrate that the strong control by miR-15a and miR-16-1 on CLL clonal expansion is exerted also at the level of full-blown leukemia and provide indications for a miRNA-based therapeutic strategy.
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: G
authors.identifier: 0000-0002-3335-1101
authors.initials: G
authors.lastname: Cutrona
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Matis
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Colombo
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Massucco
authors.affiliation: Diagnostic Imaging and Senology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: G
authors.identifier: 0000-0002-8397-5318
authors.initials: G
authors.lastname: Baio
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.|Department of Experimental Medicine, University of Genova, Genoa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Valdora
authors.affiliation: Animal Facility, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Emionite
authors.affiliation: Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Fabris
authors.affiliation: Hematology Unit, Department of Onco-Hematology, A.O. of Cosenza, Cosenza, Italy.|Biotechnology Research Unit, Aprigliano, A.O./ASP of Cosenza, Cosenza, Italy.
authors.forename: A G
authors.initials: AG
authors.lastname: Recchia
authors.affiliation: Hematology Unit, Department of Onco-Hematology, A.O. of Cosenza, Cosenza, Italy.|Biotechnology Research Unit, Aprigliano, A.O./ASP of Cosenza, Cosenza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Gentile
authors.affiliation: Diagnostic Imaging and Senology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: C E
authors.initials: CE
authors.lastname: Neumaier
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Reverberi
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Massara
authors.affiliation: Division of Histopathology and Cytopathology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Boccardo
authors.affiliation: Department of Science of Health (DISSAL), University of Genoa, Genoa, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Basso
authors.affiliation: Division of Histopathology and Cytopathology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Salvi
authors.affiliation: Department of Science of Health (DISSAL), University of Genoa, Genoa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Rosa
authors.affiliation: Animal Facility, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cilli
authors.affiliation: Molecular Diagnostic Unit, Division of Histopathology and Cytopathology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Zupo
authors.affiliation: Division of Histopathology and Cytopathology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Truini
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Salvatore Venuta University Campus, Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tassone
authors.affiliation: Diagnostic Imaging and Senology, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Calabrese
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Negrini
authors.affiliation: Hematology Unit, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.|Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Neri
authors.affiliation: Hematology Unit, Department of Onco-Hematology, A.O. of Cosenza, Cosenza, Italy.|Biotechnology Research Unit, Aprigliano, A.O./ASP of Cosenza, Cosenza, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Morabito
authors.affiliation: Department Integrated Oncological Therapies, Molecular Pathology Unit, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.|Department of Experimental Medicine, University of Genova, Genoa, Italy.
authors.forename: F
authors.identifier: 0000-0002-6643-7083
authors.initials: F
authors.lastname: Fais
authors.affiliation: Scientific Direction, IRCCS-A.O.U., San Martino-IST, Genoa, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ferrarini
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002872:Chromosome Deletion; D002882:Chromosomes, Human, Pair 13; D064593:Heterografts; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C505361:MIRN15 microRNA, human; C505362:MIRN16 microRNA, human; D035683:MicroRNAs