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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)19807-19818
Number of pages12
JournalOncotarget
Volume6
Issue number23
Publication statusPublished - 2015

Keywords

  • Chronic lymphocytic leukemia
  • Gene therapy
  • miR-181b
  • Mouse model
  • TCL1

ASJC Scopus subject areas

  • Oncology

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