Fine structure of translocation breakpoints in leukemic blasts with chromosomal translocation t(4;11): the DNA damage-repair model of translocation

Abstract

Chromosomal translocations t(4;11) are regularly associated with a specific type of acute leukemias and probably initiate the development of this disease. It has been proposed by others, that these translocations are mediated by recombinases of the immune system. The breakpoints on both derivative chromosomes for three t(4;11) leukemia-derived cell lines and primary blasts from two patients have been analysed here in detail. The results revealed that: (a) multiple double- or single-stranded DNA breaks must have occured near the translocation breakpoints on both participating chromosomes; and (b) DNA fragments flanked by these breaks must have either been deleted, inverted or duplicated during the translocation process. We found no evidence for the involvement of specific target sequences and recombinases of the immune system. Similar characteristic features were observed by re-interpretation of published t(6;11) and t(9;22) translocation data. Therefore we present a new model for the generation of these translocations which poses, that these translocations are reciprocal but not balanced at the fine structure level and that the DNA damage-repair machinery is likely involved in producing the final structure of the translocation breakpoint.