Oncotarget

Research Papers:

miR-181b as a therapeutic agent for chronic lymphocytic leukemia in the Eµ-TCL1 mouse model

Antonella Bresin, Elisa Callegari, Lucilla D’Abundo, Caterina Cattani, Cristian Bassi, Barbara Zagatti, M. Grazia Narducci, Elisabetta Caprini, Yuri Pekarsky, Carlo M. Croce, Silvia Sabbioni, Giandomenico Russo, Massimo Negrini _

PDF  |  HTML  |  Supplementary Files  |  Order a Reprint

Oncotarget. 2015; 6:19807-19818. https://doi.org/10.18632/oncotarget.4415

Metrics: PDF 774 views  |   HTML 829 views  |   ?  


Abstract

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

Correspondence to:

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

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 4415