RAS and the myelodysplastic syndromes

RAS genes have been implicated in several different malignancies. The mechanism of activation in most cases has been due to point mutations at critical domains responsible for guanine nucleotide binding. These changes alter the conformation of the protein resulting in insensitivity of the protein to the GTPase activating protein which normally hydrolyses the active p21RAS GTP-bound form to the inactive GDP-bound form. RAS genes have potent effects on the differentiation and proliferation program of cells. The mechanism induced depends on the context in which RAS is found as well as its mutational status and indeed which RAS gene family member is involved. RAS mutations have been described early in the disease process in haematologically normal individuals at risk of mutations induced by either occupational hazard exposure, such as benzene, or of secondary disease after chemotherapy for a previous malignancy. It also been associated with disease progression from myelodysplasia (MDS) to acute myelogenous leukaemia (AML), but it has also been described to be lost upon disease progression, thus showing that RAS mutations are unlikely to be initiating events or at least not required for maintenance of disease. As RAS appears to be involved in primary and secondary myeloid leukaemias, it is a good candidate for gene targeted therapeutic intervention. Studies to target RAS either directly or indirectly by interfering in the RAS pathway are underway. Clinical trials with a peptide RAS vaccine are also ongoing in solid tumours. This report seeks to review the evidence for RAS involvement as oncogenes, focusing on MDS, the reasons as to why the hot spots of codons 12/13 and 61 are particularly potent in activating the transformation potential of RAS and the different approaches being undertaken to translate laboratory findings into therapeutic reality.