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

Wessex Regional Genetics Laboratory, Salisbury and Human Genetics Division, University of Southampton School of Medicine, Southampton, UK.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K (Impact Factor: 10.43). 10/2010; 24(10):1742-50. DOI: 10.1038/leu.2010.174
Source: PubMed


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.

Download full-text


Available from: Bertrand Nadel, Mar 19, 2014
    • "Although increasing number of studies has been published in last few years678910111213141516, analysis of BCR-ABL1 at the DNA level has been limited and difficult so far. Our mLR-PCR-NGS approach streamlined the laboratory workflow for patient-specific BCR-ABL1 fusion characterization allowing personalizing real-time PCR assays for patients with MRD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In chronic myeloid leukemia, the identification of individual BCR-ABL1 fusions is required for the development of personalized medicine approach for minimal residual disease monitoring at the DNA level. Next generation sequencing (NGS) of amplicons larger than 1000 bp simplified and accelerated a process of characterization of patient-specific BCR-ABL1 genomic fusions. NGS of large regions upstream and downstream the individual breakpoints in BCR and ABL1 genes, respectively, also provided information about the sequence variants such are single nucleotide polymorphisms.
    No preview · Article · Apr 2015 · Molecular Cancer
  • Source
    • "DNA fusion sequences from adult BCR - ABL1 positive leukemia patients were retrieved from four recent publications ( Zhang et al . , 1995 ; Mattarucchi et al . , 2008 ; Score et al . , 2010 ; Bur - meister et al . , 2011 ) ( Zhang et al"
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic myeloid leukemia (CML) is a rare disease in children and adolescents and various aspects-from molecular genesis to therapy regimen-have been taken over from studies on the more prevalent adult CML. However, differences have been observed between malignancies with identical underlying chromosomal translocations, but occurring at different age groups, suggesting some diversity in the mechanisms of formation and leukemogenesis. A multiplex long-range PCR-based assay was developed to allow fast and reliable amplification of patient-specific BCR-ABL1 fusion sequences from genomic DNA. The localization of breakpoints was analyzed with respect to distribution within the breakpoint cluster regions, sequence features, and association to repetitive elements or motifs associated with DNA recombination. The genomic fusion sites of 59 pediatric CML patients showed a bimodal breakpoint distribution in BCR that was different from the distribution in adult CML cases, but with similarities to BCR-ABL1-positive, acute lymphoblastic leukemia in adults. BCR breakpoints were found more frequently positioned within, or close to, Alu repeats than would be expected based on their overall sequence proportion. Technical aspects of the highly sensitive DNA-based quantification of residual CML cells by specific fusion sequence during tyrosine kinase inhibitor therapy are exemplified in a subcohort of pediatric CML patients. © 2012 Wiley Periodicals, Inc.
    Full-text · Article · Nov 2012 · Genes Chromosomes and Cancer
  • [Show abstract] [Hide abstract]
    ABSTRACT: A 0.35μm CMOS analog decoder for a 4-state, rate 1/3, block length 16 turbo code operates at 13.3Mb/s and latency of 1.2μs and consumes 13.9nJ per decoded bit with a 3.3V supply. The 1.42mm<sup>2</sup> core IC implements two logarithmic domain MAP decoders and a fully programmable analog interleaver that is configured at power-up.
    No preview · Conference Paper · Feb 2003
Show more