Abstract 3974: A preclinical study for miR181b as therapeutic in Eu-TCL1FL-tg mouse model for CLL

Chronic lymphocytic leukemia (CLL) is a malignancy of B cells with immunophenotype of memory cells. Downstream pathways to BCR, like NFkB, AKT and ERK, and anti-apoptotic proteins such as Bcl2 and Mcl1, are thought to contribute to expansion and survival of the malignant cells. CLL patients show different clinical course: tumor clones having no V-gene mutations, many CD38+ or ZAP-70+ B cells, chromosome 11q deletion and high expression of TCL1, had an aggressive, usually fatal course, whereas patients with mutated clones, few CD38+ or ZAP-70+ B cells and low TCL1 expression, had an indolent course. Recent studies identified a microRNA signature associated with prognosis and progression in B-CLL. Particularly, miR181b is down-regulated in aggressive forms of CLL and its expression is inversely correlated to Tcl1 levels.An increasing number of studies are considering microRNAs as potentially useful therapeutic agents. Given that MCL-1, BCL-2 and TCL1 are proved targets for miR181b, that Akt activation is enhanced by Tcl1 and a crosstalk between Akt and ERK or NFkB exists, we performed a preclinical evaluation of miR181b therapeutic efficacy in a mouse model of CLL, the Eu-TCL1 transgenic mouse, previously generated by us.In vitro enforced expression of miR-181b mimics induced a significant apoptotic effect in human B-cell line 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 Mcl...

Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Bresin, A., Callegari, E., D'Abundo, L., Cattani, C., Bassi, C., Zagatti, B., Narducci, M. G., Caprini, E., Pekarsky, Y., Croce, C. M., Sabbioni, S., Negrini, M., Russo, G. Tags: Molecular and Cellular Biology Source Type: research