DNA Sequence Features of Additional Partner Chromosome-BCR Junction Fragments Associated with Complex BCR-ABL1 Rearrangements of CML
Leukaemia often happens when DNA that encodes genes at different chromosomal sites spontaneously recombines in progenitor cells of the haematopoietic system. In one subtype, chronic myeloid leukaemia (CML), the BCR-ABL1 fusion protein is responsible for the clinical phenotype, and is expressed after recombination occurs between the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9. In about 90% of CML patients, this recombination results in a cytogenetically visible, simple reciprocal exchange involving the long arms of chromosome 9 and 22. In the remaining cases, recombination between BCR and ABL1 can be more complex involving additional chromosomal sites that may be visible cytogenetically or cryptically concealed within a normal appearing chromosome complement. Previously, we isolated BCR gene fragments linked to other participating chromosomes from four patients with complex rearrangements. Unexpectedly, coding regions were found disrupted at the additional partner chromosome-BCR recombination site in two cases. A combination of inverse-PCR and DNA sequence analysis has now been applied to isolate and characterise genomic features at BCR recombination sites in a new series of 20 CML patients having complex BCR-ABL1 rearrangements. By this approach, BCR fragments linked to additional participating chromosomes have been isolated from seven further patients. Preliminary sequence analysis shows a disrupted coding region in one case at the BCR recombination site and in a further five cases the breakpoints map 95 bp and up to ~25 kb from coding domains. Additional gene involvement has potential to influence the biology and pathology of the leukaemic disease, with further study required to substantiate and extend these novel findings.