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Cloettapreis_2004_Nr_32

diagnostic tools or might hold keys to the understanding of the patho- genesis. We compared several of these markers simultaneously in a cohort of patients with MPD and found that the correlation between the markers is lower than reported (Kralovics et al., 2003). In particular, the decreased expression of c-MPL protein was present in less than half of patients with PV or ET and was also found in members of a family with a mutation in the TPO gene. This indicates that decreased c-MPL protein is not involved in the pathogenesis, but rather represents a consequence of high platelet count. Comparing patients with sporadic MPD with family members carrying a known molecular alteration proves to be very helpful for distinguishing primary alterations from secondary events. Future directions Genome wide expression studies comparing mature blood cells or pro- genitors from patients with MPD and healthy controls will undoubtedly improve our picture of the changes that occur during the evolution of MPD. We have performed a high-density microarray expression analysis on RNA from MPD patients, healthy controls and familial MPD-like syndromes and are currently analyzing the data. Methods for screening for subtle chromosomal alterations, such as genome wide microsatel- lite analysis and chip based comparative genomic hybridization, will complement these studies. One result on which we are following up is the finding of loss of heterozygosity on chromosome 9p (9pLOH), which occurs in 30% of patients with PV and constitutes the most frequent chromosomal aberration in MPD (Kralovics et al., 2003; Kralovics et al., 2002). This somatic mutation could act synergistically with a putative mutation of a gene in chr. 9q. Finally, an interesting aspect of MPD is the suppression by the MPD clone of normal hema- topoiesis from stem cells not carrying the MPD mutations. We hypo- thesize that inhibitory signals, such as the transforming growth factor beta (TGF␤) family of signaling molecules, could be mediating this effect (Figure 4). We will test this hypothesis by inactivating the TGF␤ receptors on hematopoietic cells using mouse knockout models or by applying siRNA in human hematopoietic progenitors (Schomber et al., 48

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