Studi pre-clinici per lo sviluppo di approcci terapeutici basati sui microRNA in un modello di Leucemia Linfatica Cronica

Despite its indolent nature, chronic lymphocytic leukemia (CLL) is an incurable disease. The involvement of microRNAs (miRNAs) in CLL pathogenesis has been established and it suggests that miRNAs are attractive candidates as therapeutic targets for CLL. Here, we employed the Eμ-TCL1 transgenic mouse model, which develops a chronic B-cell CD5+ leukemia similar to an aggressive form of human B-CLLs, to investigate miR-181b and miR-34a as a new therapeutic agents. In vitro, the enforced expression of miR-181b mimics induced a significant apoptotic effect in human B-cells (RAJI, DAUDI, 697, EHEB) as well as in mouse Eμ-TCL1 leukemic splenocytes. In addition molecular analyses revealed that miR-181b not only affected the expression of Tcl1, but also of Bcl2 and Mcl1 anti-apoptotic proteins, and reduced the phosphorylation levels of Akt and Erk1/2. Similarly, the restoration of miR-34a induced an increase of apoptosis in murine leukemic spleen cells, which could be related to the modulation of CDK6 and Bcl-2 targets. Finally, in vivo multiple treatments with miR-181b or miR-34a mimics induced a reduction/delay in the progression of leukemia and an increase of overall survival in treated mice. Our pre-clinical assessment of miRNA-based therapies in a CLL mouse model proves a sizable anti-leukemic activity of miR-181b and miRNA-34a as single agents, and suggests that the use of microRNAs could represent a novel potential therapeutic approach for the treatment of CLL.