MOLECULAR CHARACTERIZATION OF JUMPING TRANSLOCATIONS REVEALS SPATIAL AND TEMPORAL BREAKPOINT HETEROGENEITY

Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although J T occasionally are constitutional, most are associated with hematologi c malignancies. In such cases, JT usuary arise during disease progress ion and are associated with poor prognosis. Despite its clinical impor tance, this cytogenetic phenomenon has not been characterized at the m olecular level. We have analyzed JT in a juvenile chronic myelomonocyt ic leukemia that subsequently transformed to an acute myeloid leukemia . Detailed fluorescence in situ hybridization (FISH) analyses showed t hat the cytogenetically identical donor breakpoint at 3q21 was highly heterogeneous. In fact, more than 10 distinct breakpoints, four of whi ch mapped within YACs, were identified. Analyses of samples during dis ease progression showed that the breakpoint complexity decreased, indi cating clonal selection. Hence, the 3q21 breakpoints displayed a spati al as well as a temporal heterogeneity, revealing that JT are highly u nstable, showing great variation in the size of donor segment. The bre aks at the recipient chromosomes were mapped within the subtelomeric r egions. The general telomere length was not affected and an underlying replication error resulting in microsatellite instability was exclude d. We conclude that the emergence of JT is unlikely to cause fusion ge nes or to affect the expression of genes located in the break point re gions. The identification of YACs spanning the breakpoints, ie, YACs 9 13c7, 937g5, 948c2 and 955g1, may facilitate the isolation of DNA sequ ences leading to a genetic instability associated with the origin of m ultiple translocations.