Analysis of genomic breakpoints in p190 and p210 BCR–ABL indicate distinct mechanisms of formation
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.
1742-1750
Score, J.
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Calasanz, M.
e029a587-5851-40f7-b274-32d8b25cf1bf
Ottman, O.
46824446-fbcc-4fe7-a023-10f43c910c54
Pane, F.
f289c8fb-c198-41a7-8e08-720ef098c681
Yeh, R.F.
96f8be17-4226-4982-b53a-3a2d3334da13
Sobrinho-Simões, M.A.
fc266e98-5977-4344-a4e7-cb98b278f0c4
Kreil, S.
2404ac13-cdaa-43a3-913b-adceb79e598f
Ward, D.
9690c71a-d256-440b-bb66-22589563a9f0
Hidalgo-Curtis, C.
b492ffa5-2adb-4901-973f-72e2432b0ee0
Melo, J.V.
e3ef7550-b67a-458c-af81-5d7dd8fb1306
Wiemels, J.
b1170dd7-f1a0-444a-b34c-18e0c9bb3050
Nadel, B.
5d0d5168-66bc-4c29-b7a6-7e2f0c6d8760
Cross, N.C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Grand, F.H.
f4b9e5f4-28c4-44d2-9916-d852c2fdaef8
October 2010
Score, J.
ea0db6ef-c17e-4915-b216-ac67c07b26b7
Calasanz, M.
e029a587-5851-40f7-b274-32d8b25cf1bf
Ottman, O.
46824446-fbcc-4fe7-a023-10f43c910c54
Pane, F.
f289c8fb-c198-41a7-8e08-720ef098c681
Yeh, R.F.
96f8be17-4226-4982-b53a-3a2d3334da13
Sobrinho-Simões, M.A.
fc266e98-5977-4344-a4e7-cb98b278f0c4
Kreil, S.
2404ac13-cdaa-43a3-913b-adceb79e598f
Ward, D.
9690c71a-d256-440b-bb66-22589563a9f0
Hidalgo-Curtis, C.
b492ffa5-2adb-4901-973f-72e2432b0ee0
Melo, J.V.
e3ef7550-b67a-458c-af81-5d7dd8fb1306
Wiemels, J.
b1170dd7-f1a0-444a-b34c-18e0c9bb3050
Nadel, B.
5d0d5168-66bc-4c29-b7a6-7e2f0c6d8760
Cross, N.C.P.
f87650da-b908-4a34-b31b-d62c5f186fe4
Grand, F.H.
f4b9e5f4-28c4-44d2-9916-d852c2fdaef8
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), .
(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.
This record has no associated files available for download.
More information
Accepted/In Press date: 12 August 2010
Published date: October 2010
Identifiers
Local EPrints ID: 162257
URI: http://eprints.soton.ac.uk/id/eprint/162257
ISSN: 0887-6924
PURE UUID: 37232fd5-8c93-4fc4-b008-0b07e2661ac8
Catalogue record
Date deposited: 17 Aug 2010 11:21
Last modified: 14 Mar 2024 02:46
Export record
Altmetrics
Contributors
Author:
J. Score
Author:
M. Calasanz
Author:
O. Ottman
Author:
F. Pane
Author:
R.F. Yeh
Author:
M.A. Sobrinho-Simões
Author:
S. Kreil
Author:
D. Ward
Author:
C. Hidalgo-Curtis
Author:
J.V. Melo
Author:
J. Wiemels
Author:
B. Nadel
Author:
F.H. Grand
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics