title: miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model.
abstract: The involvement of microRNAs (miRNAs) in chronic lymphocytic leukemia (CLL) pathogenesis suggests the possibility of anti-CLL therapeutic approaches based on miRNAs. Here, we used the Eµ-TCL1 transgenic mouse model, which reproduces leukemia with a similar course and distinct immunophenotype as human B-CLL, to test miR-181b as a therapeutic agent.In vitro enforced expression of miR-181b mimics induced significant apoptotic effects in human B-cell lines (RAJI, EHEB), as well as in mouse Eµ-TCL1 leukemic splenocytes. Molecular analyses revealed that miR-181b not only affected the expression of TCL1, Bcl2 and Mcl1 anti-apoptotic proteins, but also reduced the levels of Akt and phospho-Erk1/2. Notably, a siRNA anti-TCL1 could similarly down-modulate TCL1, but exhibited a reduced or absent activity in other relevant proteins, as well as a reduced effect on cell apoptosis and viability. In vivo studies demonstrated the capability of miR-181b to reduce leukemic cell expansion and to increase survival of treated mice.These data indicate that miR-181b exerts a broad range of actions, affecting proliferative, survival and apoptotic pathways, both in mice and human cells, and can potentially be used to reduce expansion of B-CLL leukemic cells.
authors.affiliation: Università di Ferrara, Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Ferrara, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Bresin
authors.affiliation: Università di Ferrara, Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Ferrara, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Callegari
authors.affiliation: Università di Ferrara, Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Ferrara, Italy.
authors.forename: Lucilla
authors.initials: L
authors.lastname: D'Abundo
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Laboratorio di Oncologia Molecolare, Rome, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Cattani
authors.affiliation: Università di Ferrara, Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Ferrara, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Bassi
authors.affiliation: Università di Ferrara, Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Ferrara, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Zagatti
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Laboratorio di Oncologia Molecolare, Rome, Italy.
authors.forename: M Grazia
authors.initials: MG
authors.lastname: Narducci
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Laboratorio di Oncologia Molecolare, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Caprini
authors.affiliation: Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, OSU School of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pekarsky
authors.affiliation: Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, OSU School of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.affiliation: Università di Ferrara, Dipartimento di Scienze della Vita e Biotecnologie, Ferrara, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sabbioni
authors.affiliation: Istituto Dermopatico dell'Immacolata, IDI-IRCCS, Laboratorio di Oncologia Molecolare, Rome, Italy.
authors.forename: Giandomenico
authors.initials: G
authors.lastname: Russo
authors.affiliation: Università di Ferrara, Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Ferrara, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Negrini
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014162:Transfection
chemical_list: D051017:Apoptosis Regulatory Proteins; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: TCL1; chronic lymphocytic leukemia; gene therapy; miR-181b; mouse model