MicroRNAs (miRNA) are small (1824 nts) non-coding RNAs which are part of an evolutionarily highly conserved intracellular mechanism to regulate gene expression in a sequence-specific manner. These regulatory RNAs function by acting as sequence-specific guides which recruit multi-protein complexes to target mRNA sequences which are subsequently silenced. miRNAs are processed from primary transcripts (pri-miRNA) by cellular components which are also at least partially involved in the process of RNA interference (RNAi). Various functions have been attributed to miRNAs including regulation of cellular proliferation, differentiation, and apoptosis. Moreover, aberrant expression of specific miRNAs has recently been described in human lymphoma and leukemia. In particular, BCR-ABL and c-MYC dependent over-expression of the polycistronic and oncogenic miR-17-92 cluster (encoding miR-17, miR-18a, miR-19a, miR-20a, miR-19b, and miR-92) has been described in chronic myeloid leukemia (CML) cell lines, primary CD34+ cells from CML patients, and in lung cancer. Moreover, in BCR-ABL positive K562 cells, miR-17-92 encoded miRNAs repress luciferase activity in miRNA-specific reporter assays. In addition, lentivirus-mediated over-expression of miR-17-92 increases both cell proliferation and sensitivity to imatinib induced cell death. So far, the function of and the targets regulated by individual miRNAs, in particular of those encoded on polycistronic transcripts, are largely unknown. Finally, strategies to induce stable gain- and loss-of-function phenotypes for specific miRNAs based on lentiviral transfer of miRNA- and antagomir expression cassettes will allow functional analysis of individual miRNAs. Such studies are required to determine whether altered miRNA expression may contribute to the pathophysiology of CML and how miRNAs may provide potential targets for therapeutic intervention.
03 - 07 May 2008
European Society of Endocrinology