Argonaute 2 as novel molecular determinant for myeloid differentiation

Abstract

microRNAs (miRNAs) are emerging as crucial factors for the establishment of complex regulatory circuitries involved in the regulation of hematopoietic cell fate determination. These small non-coding RNAs to exert their functional activity are assembled in RNA-induced silencing complexes (RISCs), where a member of Argonaute (Ago) family of proteins plays a central role in miRNA-mRNA target interaction and gene silencing. In human cells the miRNAs-Ago complex can also localize in the nucleus where Ago proteins can associate with promoter gene sequences to impact heterochromatin genomic structure and transcriptional silencing (Janowski BA et al., 2006; Meister G., 2013). By using human myeloid cell lines and acute myeloid leukemia (AML) primary blasts we highlight Ago2 as a new player in myeloid cell fate determination. We observed that: i) Ago2 protein levels are strongly increased during 1,25-dihydroxyvitamin D3 (D3)-induced monocyte differentiation, whereas are down-regulated during Retinoic Acid (RA)-induced granulocyte differentiation; ii) Ago2 depletion by shRNA or small chemical compounds disrupting both miRNA-Ago2 complex interaction and Ago2 chromatin localization, results in a strong improvement of the RA-dependent myeloid differentiation. These results are bringing out that the down-regulation of Ago2 expression/functional activity is required during RA-dependent myeloid differentiation and may represent a molecular determinant for the improvement of RA-treatment response in leukemic myeloid progenitors cells.