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Cloettapreis_2004_Nr_32

serum TPO levels, but normal red blood cell and normal leukocyte counts. The penetrance is usually 100%, the clinical course is mild with occasional thrombotic or bleeding complications, but without leukemic transformation. In all cases studied, overproduction of TPO is caused by a mechanism of increased translational efficiency for the mutant TPO mRNA (Ghilardi and Skoda, 1999; Ghilardi et al., 1999; Wiestner et al., 1998). These mutations constitute paradigms of translational pathophysiology and are examples of a novel molecular mechanism of human diseseas (Cazzola and Skoda, 2000). Mutations in TPO have not been found in patients with sporadic MPD (Harrison et al., 1998; Taksin et al., 1999). Therefore, thrombocythemia due to gain of func- tion mutations in the TPO gene constitutes a phenocopy of sporadic ET. Whereas mutations in TPO account for only approx. 20% of familial thrombocytosis (Kunishima et al., 1998; Wiestner et al., 2000), the disease-causing gene still remains unknown in all other cases. Thus, mutations in one or several additional genetic loci can also cause thrombocytosis. Genetic analysis in these families will allow us to identify new components that regulate megakaryopoiesis. The pheno- type in some of the families resembles sporadic forms of MPD. We found clonal hematopoiesis in the affected individuals, indicating that a somatic mutation acts in synergy with a predisposition inherited through the germline. The search for the mutated gene in families, which display a phenotype very closely resembling sporadic MPD, appears particularly worthwhile and we expect that the mutated gene will also be of relevance for patients with sporadic MPD. In one large pedigree with MPD-like phenotype, we have located the gene to chro- mosome 9q and are now searching for the mutation in genes that lie within the co-segregating interval (Kralovics et al, in preparation). Our studies suggest that at least two hits are necessary for phenotypic mani- festation of MPD: a pre-disposing mutation in a gene on chromosome 9q and a somatic mutation in a second locus (Figure 4). Studies on sporadic MPD revealed a number of new molecular markers, such as decreased expression of c-MPL protein in platelets (Moliterno et al., 1998) and PRV-1 mRNA in granulocytes (Temerinac et al., 2000). These alterations in the expression pattern could be valuable as 47

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