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Cloettapreis_2004_Nr_32

numbers of non-lymphoid cells and/or platelets in the peripheral blood. In addition to thrombotic and hemorrhagic complications, leukemic transformation can occur. The classical definition of MPD included four disease entities, which were thought to be related (Damashek, 1951): chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (IMF). The Philadelphia chromosome and the bcr/abl fusion transcripts established CML as a separate entity, allowed developing diagnostic PCR tests and made it possible to derive a specific tyrosine kinase inhib- itor (Imatinib/ Glivec), which is used successfully in the treatment of CML patients. The cause of the three remaining forms of MPD remains unknown, but progress has been made in defining the functional and molecular characteristics of MPD. The investigation of inherited dis- orders resembling MPD complements these studies and provides important clues to the hierarchy of events in the pathogenesis of MPD. The finding that TPO and its receptor exert strong lineage selective effects on platelet production suggested that mutations in TPO or c-mpl could play a role in disorders with increased or decreased megakar- yopoiesis. Inherited disorders are particularly suited to test such a hypo- thesis, because the involvement of a candidate gene locus can be confirmed or excluded by genetic linkage analysis. In a family with autosomal dominant thrombocytosis resembling ET, we were able to locate the disease-causing gene to the TPO locus on chromosome 3q and to find a mutation in the TPO gene (Wiestner et al., 1998). The mechanism of how this mutation causes elevated TPO serum levels was at first quite difficult to understand. Affected family members carry a point mutation in the +1 position of the splice donor of intron 3. This mutation causes exon-skipping and results in loss of exon 3, including the nucleotides encoding the first 4 amino acids of the TPO protein. This mutation appeared to cause a loss of function of the TPO allele, thus, the opposite of what we had expected. However, more detailed analysis revealed that a novel N-terminus is created by fusion with an upstream open reading frame and we could show that the extended N-terminus behaves as a functional signal peptide. Importantly, the mutation results in TPO overproduction due to removal of sequences contained within exon 3 that normally inhibit the translation of TPO 45

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