RNA interference as a potential tool in the treatment of leukaemia

Abstract

Leukaemias are often characterised by nonrandom chromosomal translocations that, at the molecular level, induce the activation of specific oncogenes or create novel chimeric genes. They have frequently been regarded as optimal targets for gene silencing approaches, as these single abnormalities may directly initiate or maintain the malignant process. Since the ground-breaking discovery that double-stranded RNA molecules 21 - 23 nucleotides in length, named small interfering RNAs (siRNAs), are able to elicit gene-specific inhibition also in mammalian cells, the interest of the scientific community has rapidly been drawn to the potential of these siRNAs for targeting oncogenic fusion genes in leukaemic cells. There has been a flurry of reports describing overexpressed or mutated genes that may also serve as attractive targets for therapeutic intervention by RNA silencing methods. Although this approach seems to be relatively straightforward, many problems remain to be solved before siRNAs may become clinically implemented as 'leukaemia drugs'. Difficulties in delivering siRNAs into the leukaemic cell, inefficient target mRNA cleavage, prolonged protein half-life in cancer cells, nonspecific side effects caused by targeting other genes than those originally thought, immunological reactions of the host organism against the siRNAs, such as interferon responses, or even acquired resistance mechanisms, such as escape mutants, should be overcome. This paper reviews the current knowledge regarding the use of siRNAs, either chemically synthesised or intracellular-generated via specialised expression constructs, in order to suppress the falsely activated oncogenes in haematopoietic malignancies.