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

Autores: Score, J.; Calasanz Abinzano, María José; Ottman, O.; Pane, F.; Yeh, R. F.; Sobrinho-Simoes, M. A.; Kreil, S.; Ward, D.; Hidalgo-Curtis, C.; Melo, J. V.; Wiemels, J.; Nadel, B.; Cross, N. C.; Grand, F. H.
Título de la revista: LEUKEMIA
ISSN: 0887-6924
Volumen: 24
Número: 10
Páginas: 1742 - 1750
Fecha de publicación: 2010
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.