Pathogenesis of jumping translocations: a molecular cytogenetics study

Jumping translocations are rare cytogenetic aberrations in haematological malignancies, the pathogenesis of which remains to be fully characterised. We investigated the mechanism of formation of jumping translocations in a case of adult common acute lymphoblastic leukaemia (ALL) positive for the Ph translocation.

Interphase and metaphase fluorescence in situ hybridisation (FISH) was performed using several probe systems. Results were correlated with findings on conventional cytogenetics. Granulocytes, T-cells and leukaemic B-cells in peripheral blood were sorted by immunomagnetic method and the terminal restriction fragment (TRF) length of these cellular populations was determined by Southern blot analysis.

Duplicated BCR-ABL fusion signals were found on a dic(14;22)der(22)t(9;22) chromosome. Clonal jumping translocations, existing as evolutionary changes, involved the donor chromosomal segment distal to 1q12 jumping onto the telomere ends of 11q, 15p, 19p and 20p. Telomere length was decreased in the neoplastic B-cell population and contributed to the formation of the dicentric chromosome that showed absence of telomere repeats at fusion ends. Subsequent pericentromeric heterochromatin decondensation of chromosome 1q occurred, and this donor segment was randomly fused to the shortened telomere ends of non-homologous chromosomes.

Both telomere shortening and pericentromeric heterochromatin decondensation contribute to the formation of jumping translocations, which is most probably a multi-stage process.