Analysis of genomic breakpoints in p190 and p210 BCR-ABL indicate distinct mechanisms of formation.
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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Wessex Regional Genetics Laboratory, Salisbury and Human Genetics Division, University of Southampton School of Medicine, Southampton, UK.
Calasanz
M J
MJ
Ottman
O
O
Pane
F
F
Yeh
R F
RF
Sobrinho-Simões
M A
MA
Kreil
S
S
Ward
D
D
Hidalgo-Curtis
C
C
Melo
J V
JV
Wiemels
J
J
Nadel
B
B
Cross
N C P
NC
Grand
F H
FH
D001483:Base Sequence; D056905:Chromosome Breakpoints; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012689:Sequence Homology, Nucleic Acid; D014178:Translocation, Genetic
D018398:Homeodomain Proteins; C064658:RAG-1 protein; D016044:Fusion Proteins, bcr-abl