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Cytogenetics and Molecular Genetics

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

Abstract

We sought to understand the genesis of the t(9;22) by characterizing genomic breakpoints in chronic myeloid leukemia (CML) and BCR–ABL-positive acute lymphoblastic leukemia (ALL). BCR–ABL breakpoints were identified in p190 ALL (n=25), p210 ALL (n=25) and p210 CML (n=32); reciprocal breakpoints were identified in 54 cases. No evidence for significant clustering and no association with sequence motifs was found except for a breakpoint deficit in repeat regions within BCR for p210 cases. Comparison of reciprocal breakpoints, however, showed differences in the patterns of deletion/insertions between p190 and p210. To explore the possibility that recombinase-activating gene (RAG) activity might be involved in ALL, we performed extra-chromosomal recombination assays for cases with breakpoints close to potential cryptic recombination signal sequence (cRSS) sites. Of 13 ALL cases tested, 1/10 with p190 and 1/3 with p210 precisely recapitulated the forward BCR–ABL breakpoint and 1/10 with p190 precisely recapitulated the reciprocal breakpoint. In contrast, neither of the p210 CMLs tested showed functional cRSSs. Thus, although the t(9;22) does not arise from aberrant variable (V), joining (J) and diversity (D) (V(D)J) recombination, our data suggest that in a subset of ALL cases RAG might create one of the initiating double-strand breaks.

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Acknowledgements

This work was funded by Leukaemia and Lymphoma Research (UK); JS was supported by a Gordon Piller PhD Studentship.

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Correspondence to N C P Cross.

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The study was designed by JS, NCPC and FHG. Laboratory analysis was performed by JS, MAS-S, SK, CH-C, DW. Data analysis was performed by JS, RFY, JW, BN. Samples and data were provided by MJC, OO, FP, MAS-S, JVM. The initial paper was written by JS, NCPC and FHG; all authors contributed to the final version.

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Score, J., Calasanz, M., Ottman, O. et al. Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation. Leukemia 24, 1742–1750 (2010). https://doi.org/10.1038/leu.2010.174

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