Mutations in the p53 and RAS genes have been observed in a small proportion of patients with an MPD. However, most such mutations were found in patients with a later or acute phase of the disease. Therefore, mutations of p53 and RAS genes are more frequently associated with disease progression and transformation to acute leukemia rather than initiation of the MPD itself.
In addition to positional cloning strategies, several other approaches are being pursued to identify genetic defects that contribute to the pathogenesis of MPD. One approach is to search for differentially expressed genes between cells from normal individuals and PV patients. This approach has a number of inherent problems. Progenitor cell populations are heterogeneous, so differences in gene expression may be secondary to shifts in the composition of the progenitor cell compartment. Comparison of neutrophils uses a more homogeneous population but is unlikely to identify primary pathogenetic changes. Secondly, genes that are affected by point mutations but whose expression level is unchanged will not be identified. However, even if the primary target is not identified, this approach may uncover consistent secondary changes which may be helpful diagnostically and shed light on the altered behavior of progenitor cells in PV. Such an approach was used to identify the overexpression of PRV-1 in PV granulocytes.
Work in the authors' laboratory is supported by the Leukaemia Research Fund, the Medical Research Council and the Wellcome Trust.
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