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

Abstract

Dysregulation of microRNAs (miRNAs) plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). The Eμ-TCL1 transgenic mouse develops a form of leukemia that is similar to the aggressive type of human B-CLL, and this valuable model has been widely used for testing novel therapeutic approaches. Here, we adopted this model to investigate the potential effects of miR-26a, miR-130an and antimiR-155 in CLL therapy. Improved delivery of miRNA molecules into CLL cells was obtained by developing a novel system based on lipid nanoparticles conjugated with an anti-CD38 monoclonal antibody. This methodology has proven to be highly effective in delivering miRNA molecules into leukemic cells. Short- and long-term experiments showed that miR-26a, miR-130a and anti-miR-155 increased apoptosis after in vitro and in vivo treatment. Of this miRNA panel, miR-26a was the most effective in reducing leukemic cell expansion. Following long-term treatment, apoptosis was readily detectable by analyzing cleavage of PARP and caspase-7. These effects could be directly attributed to miR-26a, as confirmed by significant downregulation of its proven targets, namely cyclin-dependent kinase 6 and Mcl1. The results of this study are relevant to two distinct areas. The first is related to the design of a technical strategy and to the selection of CD38 as a molecular target on CLL cells, both consenting efficient and specific intracellular transfer of miRNA. The original scientific finding inferred from the above approach is that miR-26a can elicit in vivo anti-leukemic activities mediated by increased apoptosis.

Alteration in miRNAs expression in paediatric acute lymphocyticleukaemia: Insight into patients' therapeutic response

“…expansion of leukaemic cells by promoting apoptosis 33. Our data showed a similar expression level of miR-26a in ALL patients and controls.…”

MicroRNA‐26a inhibits multiple myeloma cell growth by suppressing cyclin‐dependent kinase 6 expression

“…26 In leukemia cells, miR-26a significantly down-regulated its proven targets, such as MCL-1, and elicited anti-leukemic activities mediated by increased apoptosis in vivo. 27 In this study, we found that overexpression of miR-26a inhibited cell growth of MM cells both in vitro and in vivo (Figures 1 and 2). It is known that cell cycle controls the cell growth, and then we assessed the cell cycle of the cells transfected with miR-26a mimic by flow cytometry.…”

“…MiR‐26a was also down‐regulated in the clinical specimens of RCC, and significantly inhibited RCC cell migration and invasion by regulating the collagen cross‐linking enzymes LOXL2 and PLOD2 . In leukemia cells, miR‐26a significantly down‐regulated its proven targets, such as MCL‐1, and elicited anti‐leukemic activities mediated by increased apoptosis in vivo …”

The involvement of microRNA in the pathogenesis of Richter syndrome

“…miR-26a reduces the expansion/accumulation of leukemic cells of Eμ-TCL1 mice and in vivo administration of miR-26a promotes apoptosis in mice. 50…”