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

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.

Anti-leukemic activity of microRNA-26a in a chronic lymphocytic leukemia mouse model

“…Leukemic cells of the Eμ-TCL1FL transgenic mouse are CD38+. Leukemic cells of the Eμ-TCL1FL transgenic mouse or transplanted into syngeneic FVB mice are characterized by B220+/CD5dim surface markers (28). Here, we evaluated the expression of CD38.…”

“…These studies established the groundwork from which miRNA-based therapies, either by restoring or repressing miRNA activity, could be designed and tested. We have already investigated miR-181b as a potential therapeutic molecule against leukemias of the TCL1-tg mouse model (28). The study proved that this miRNA induced a measurable anti-leukemic effect.…”

The interplay of LncRNA ANRIL and miR‐181b on the inflammation‐relevant coronary artery disease through mediating NF‐κB signalling pathway

“…PC‐3), and transfecting miR‐181b anti‐sense nucleotide sequences into PC‐3 cell line could result in increased cell apoptosis, decreased cell proliferation and inhibited cell invasion. Also it was covered by Bresin et al46 that over‐expressed miR‐181b might lower the expression of anti‐apoptosis proteins (eg, TCL1, Bcl2 and Mcl1) within chronic lymphocytic leukaemia (CLL) cells, and meanwhile, CLL cells’ apoptosis was evidently induced. Besides, miR‐181b expression was markedly up‐regulated within thyroid papillary carcinoma (TPC) tissues, and down‐regulating miR‐181b expression could evidently hinder TPC cells’ proliferation and promoted their apoptosis 47.…”

Novel Mechanisms of Regulation of miRNAs in CLL

“…Downregulation of miR-29 and miR-181b in aggressive CLL contributes to overexpression of Tcl1. Furthermore, study of miR-181b and miR-17/92 may provide useful insights into drug design, delivery, resistance mechanisms, and microenvironmental responses [70–72]. Given these results, we can conclude that microRNAs have a deep impact on CLL development/progression (Table 1).…”

“…Thus, the anti-leukemic effect of miR-181b can be effective also for not TCL1 -driven CLLs. Furthermore, in vivo studies demonstrated that miR-181b reduces leukemic cell expansion and increases mice survival [70]. Lastly, a synergic effect of miR-181b with fludarabine was observed in human primary CLL cells [71], providing an additional evidence for a potential role of miR-181b as a therapeutic agent in CLL.…”