miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model
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Antonella Bresin1, Elisa Callegari1, Lucilla D’Abundo1, Caterina Cattani2, Cristian Bassi1, Barbara Zagatti1, M. Grazia Narducci2, Elisabetta Caprini2, Yuri Pekarsky3, Carlo M. Croce3, Silvia Sabbioni4, Giandomenico Russo2 and Massimo Negrini1
1 Università di Ferrara, Dipartimento di Morfologia, Chirurgia e Medicina Sperimentale, Ferrara, Italy
2 Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Laboratorio di Oncologia Molecolare, Rome, Italy
3 Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, OSU School of Medicine, Ohio State University, Columbus, OH, USA
4 Università di Ferrara, Dipartimento di Scienze della Vita e Biotecnologie, Ferrara, Italy
Massimo Negrini, email:
Giandomenico Russo, email:
Keywords: chronic lymphocytic leukemia, miR-181b, TCL1, mouse model, gene therapy
Received: January 31, 2015 Accepted: May 29, 2015 Published: June 10, 2015
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.
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