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

Score, J., Calasanz, M., Ottman, O., Pane, F., Yeh, R.F., Sobrinho-Simões, M.A., Kreil, S., Ward, D., Hidalgo-Curtis, C., Melo, J.V., Wiemels, J., Nadel, B., Cross, N.C.P. and Grand, F.H. (2010) Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation. Leukemia, 24 (10), 1742-1750. (doi:10.1038/leu.2010.174). (PMID:20703256)

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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Contributors

Author: N.C.P. Cross

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