GENOM IC ANALYSIS OF (1;7) TRANSLOCATION AND del(7q) IN MYELODYSPLASTIC SYNDROME

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The unbalanced translocation t(1;7)(q10;p10) and the del(7q) are recurrent chromosomal aberrations found in myelodysplastic syndrome (MDS) and predicts a very poor prognosis. Thus, o improve (heir treatment outcome, it is of particular importance to disclose the molecular pathogenesis of these critical abnormalities, which is our research goal. In (his study we performed genetic analyses of these translocation and deletion, in an attempt to identify the critical gene(s) involved in these aberrations. First, using quantitative FISH analysis using two centromere alphoid probe, DIZ7 and D7ZI from the centromere 1q chromosome I and 7, respectively, we revealed that these two alphoids are directly involved in t(1;7) translocation. Combined with other results, it is postulated that this translocation is generated as a result of misconnect between these. highly homologous alphoids during a recombinational repair process. It is also suggested that Trisomy 1q and monosomy 7q, rather than breakpoint genes are responsible to the pathogenesis. For the targets of del(7q), we performed an comprehensive methylation analysis of CpG islands on 7q, in which a total of 130 CpG islands (60% of all CpG islands on 7q) successfully amplified by bisulfite-PCR were examined for their aberrant methylation using direct sequencing for a number of hematopoietic tumor samples including MDS. Two genes were identified which exist down stream of highly and frequently methlated CpG islands and whose expression was down regulated in a methylation-dependent manner. These are though to be candidates of tumor suppressor genes that is relevant to pathogenesis of MDS with loss of 7q materials and a mutation analysis involving a large number of MDS samples is in progress.