The BCR gene recombines preferentially with Alu elements in complex BCR- ABL translocations of chronic myeloid leukaemia

Abstract

Chronic myeloid leukaemia (CML) develops when two genes, BCR on chromosome 22 and ABL on chromosome 9, recombine to form a hybrid BCR-ABL gene with leukaemogenic properties. The mechanism which underlies this recombination is unknown, but additional chromosome sites may be involved to form complex BCR-ABL rearrangements. The majority of breakpoints in BCR occur within a 5 kb major breakpoint cluster region, M-Bcr. Here, we show that the 3' part of M-Bcr recombined within, or immediately adjacent to, Alu elements at the additional sites in all five complex BCR-ABL rearrangements that have been examined so far. This is a new finding which suggests that Alu sequences have an affinity for the BCR-ABL recombination process in complex rearrangements, and provides additional evidence for the association of these elements with somatic rearrangements which cause human leukaemia. We further show that sequence motifs similar to IgH switch pentamers and consensus binding sites of the lymphoid-associated Translin protein are present on one or more participating strands at 3'M-Bcr recombination sites. Motifs similar to Translin-binding sites were also identified within the Alu consensus. Expressed sequences mapped close to the breakpoint sites on other chromosomes in three of the five cases examined.

Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles

“…SINEs, LINEs, and Alu elements have been implicated in chromosomal translocation in human tumors (Onno et al 1992;Rudiger et al 1995;Jeffs et al 1998;Hill et al 2000). We found no evidence for such repetitive elements at the breakpoints.…”

Attempts to detect retrotransposition and de novo deletion of Alus and other dispersed repeats at specific loci in the human genome

“…3 ± 5 Both types of event are thought to occur mainly in the germline, 2 though examples of both have been observed in somatic tissues. 3,6 There is evidence that at least some unequal exchange events may be due to meiotic recombination. 4 To date, such insertions and re-arrangements have only been characterised in patients, resulting in considerable uncertainties about the nature of these processes.…”

Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation

“…This contrasts with other publications that have indicated an association of repeats, particularly Alu elements, in both ABL and BCR. 5,9 These previous observations, however, were made on small numbers of cases and may have been biased owing to the fact that the methodology used to amplify breakpoints required the presence of specific restriction enzyme recognition sites.…”

“…7,8 Nevertheless, studies in CML have noted that BCR-ABL breakpoints are often associated with repeat regions. 5,6,9,10 Also, it has been observed that BCR and ABL tend to be in close proximity compared with control genes during cell division in hematopoietic stem cells, potentially providing the opportunity for aberrant recombination should breakage occur. 3 The mechanisms behind many chromosomal translocations in lymphoid malignancies are clearer and are believed to be the result of the aberrant activity of the machinery for V(D)J or class switch recombination.…”