Molecular characterization of jumping translocations reveals spatial and temporal breakpoint heterogeneity

Abstract

Jumping translocations (JT) are characterized by the relocalization of the same part of a donor to several recipient chromosomes. Although JT occasionally are constitutional, most are associated with hematologic malignancies. In such cases, JT usually arise during disease progression and are associated with poor prognosis. Despite its clinical importance, this cytogenetic phenomenon has not been characterized at the molecular level. We have analyzed JT in a juvenile chronic myelomonocytic leukemia that subsequently transformed to an acute myeloid leukemia. Detailed fluorescence in situ hybridization (FISH) analyses showed that the cytogenetically identical donor breakpoint at 3q21 was highly heterogeneous. In fact, more than 10 distinct breakpoints, four of which mapped within YACs, were identified. Analyses of samples during disease progression showed that the breakpoint complexity decreased, indicating clonal selection. Hence, the 3q21 breakpoints displayed a spatial as well as a temporal heterogeneity, revealing that JT are highly unstable, showing great variation in the size of donor segment. The breaks at the recipient chromosomes were mapped within the subtelomeric regions. The general telomere length was not affected and an underlying replication error resulting in microsatellite instability was excluded. We conclude that the emergence of JT is unlikely to cause fusion genes or to affect the expression of genes located in the breakpoint regions. The identification of YACs spanning the breakpoints, ie, YACs 913c7, 937g5, 948c2 and 955g1, may facilitate the isolation of DNA sequences leading to a genetic instability associated with the origin of multiple translocations.

Karyotypic dissection of Hodgkin's disease cell lines reveals ectopic subtelomeres and ribosomal DNA at sites of multiple jumping translocations and genomic amplification

“…54 We also found a stable, complex rearrangement -a four-way translocation and inversion -in a pre-B ALL cell line (REH) dedicated to non-reciprocal fusion of TEL with AML1, 55 supporting the inference that complex changes in HDLM cells, eg, the putative five-way t(8;2;13;22;14) might also be facilitatory. Several reports link JT with interstitial telomere sequences, 56,57 whether random as suggested by Andreasson et al 58 or facilitatory as implied by the current report. Both (p/q) interstitial telomeres of chr.…”

Jumping translocation in acute leukemia of myelomonocytic lineage: a case report and review of the literature

“…17 One other unclassified AML case following juvenile chronic myelomonocytic leukemia has been reported. 18 We report on another JT in a case of AML5 after a 5-year untreated chronic myelomonocytic leukemia. In this case, we did not perform karyotyping at diagnosis of myelodysplasia and we cannot assume that JT was acquired at the time of AML transformation.…”

“…Three other donor chromosomes have been reported: 7q in a case of lymphoid blast crisis of CML, 3q and 11q in other cases of AML. 8,10,11,18 The recipient region is most often telomeric or subtelomeric containing repetitive sequences which are known to enable recombination. During cell proliferation, the telomeric length decreases on each cell division leading to chromosome instability unless telomerase activity is reactiv-…”

Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms

“…It has been suggested that the formation of JTs may be triggered by viral infections resulting in fusions between homologous virus-related sequences of different chromosomes (Andreasson et al, 1998). An alternative proposal has been made by Sawyer et al (1998) regarding the formation of JTs observed in multiple myeloma cases.…”