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Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer

Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer
Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer
The search for target genes involved in unbalanced acquired chromosomal abnormalities has been largely unsuccessful, because the breakpoints of these rearrangements are too variable. Here, we use the example of dicentric chromosomes in B cell precursor acute lymphoblastic leukemia to show that, despite this heterogeneity, single genes are targeted through a variety of mechanisms. FISH showed that, although they were heterogeneous, breakpoints on 9p resulted in the partial or complete deletion of PAX5. Molecular copy number counting further delineated the breakpoints and facilitated cloning with long-distance inverse PCR. This approach identified 5 fusion gene partners with PAX5: LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1 (20q11.1), KIF3B (20q11.21), and C20orf112 (20q11.1). In each predicted fusion protein, the DNA-binding paired domain of PAX5 was present. Using quantitative PCR, we demonstrated that both the deletion and gene fusion events resulted in the same underexpression of PAX5, which extended to the differential expression of the PAX5 target genes, EBF1, ALDH1A1, ATP9A, and FLT3. Further molecular analysis showed deletion and mutation of the homologous PAX5 allele, providing further support for the key role of PAX5. Here, we show that specific gene loci may be the target of heterogeneous translocation breakpoints in human cancer, acting through a variety of mechanisms. This approach indicates an application for the identification of cancer genes in solid tumours, where unbalanced chromosomal rearrangements are particularly prevalent and few genes have been identified. It can be extrapolated that this strategy will reveal that the same mechanisms operate in cancer pathogenesis in general.
0027-8424
17050-17054
An, Qian
6766de29-63b7-45eb-b21a-04cac9921373
Wright, Sarah L.
56f2b242-4d7d-46be-838b-9064ff96d152
Konn, Zoë J.
525b4648-7c88-488a-aefa-0018ac485eb4
Matheson, Elizabeth
1794dbcb-52c3-4c16-8984-88bb06ac7322
Minto, Lynne
4ffd3f1d-ffba-40d5-bb99-c1098dcb494b
Moorman, Anthony V.
e4ced178-ee03-47ef-bc5e-25d8453951d5
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Griffiths, Mike
f147af96-79ab-43ef-984c-550407b82c39
Ross, Fiona M.
ec0958f8-b992-4e4a-b7e3-c474600390ba
Davies, Teresa
7feaa1c8-4ab7-4ac9-b350-136c8bc4af34
Hall, Andy G.
ba5c3115-a875-44ed-87f7-61d0cbdb6e99
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Irving, Julie A.
94a0fe3e-5344-4523-aa2a-98969f5c6ebd
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
An, Qian
6766de29-63b7-45eb-b21a-04cac9921373
Wright, Sarah L.
56f2b242-4d7d-46be-838b-9064ff96d152
Konn, Zoë J.
525b4648-7c88-488a-aefa-0018ac485eb4
Matheson, Elizabeth
1794dbcb-52c3-4c16-8984-88bb06ac7322
Minto, Lynne
4ffd3f1d-ffba-40d5-bb99-c1098dcb494b
Moorman, Anthony V.
e4ced178-ee03-47ef-bc5e-25d8453951d5
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Griffiths, Mike
f147af96-79ab-43ef-984c-550407b82c39
Ross, Fiona M.
ec0958f8-b992-4e4a-b7e3-c474600390ba
Davies, Teresa
7feaa1c8-4ab7-4ac9-b350-136c8bc4af34
Hall, Andy G.
ba5c3115-a875-44ed-87f7-61d0cbdb6e99
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Irving, Julie A.
94a0fe3e-5344-4523-aa2a-98969f5c6ebd
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f

An, Qian, Wright, Sarah L., Konn, Zoë J., Matheson, Elizabeth, Minto, Lynne, Moorman, Anthony V., Parker, Helen, Griffiths, Mike, Ross, Fiona M., Davies, Teresa, Hall, Andy G., Harrison, Christine J., Irving, Julie A. and Strefford, Jon C. (2008) Variable breakpoints target PAX5 in patients with dicentric chromosomes: a model for the basis of unbalanced translocations in cancer. Proceedings of the National Academy of Sciences, 105 (44), 17050-17054. (doi:10.1073/pnas.0803494105). (PMID:18957548)

Record type: Article

Abstract

The search for target genes involved in unbalanced acquired chromosomal abnormalities has been largely unsuccessful, because the breakpoints of these rearrangements are too variable. Here, we use the example of dicentric chromosomes in B cell precursor acute lymphoblastic leukemia to show that, despite this heterogeneity, single genes are targeted through a variety of mechanisms. FISH showed that, although they were heterogeneous, breakpoints on 9p resulted in the partial or complete deletion of PAX5. Molecular copy number counting further delineated the breakpoints and facilitated cloning with long-distance inverse PCR. This approach identified 5 fusion gene partners with PAX5: LOC392027 (7p12.1), SLCO1B3 (12p12), ASXL1 (20q11.1), KIF3B (20q11.21), and C20orf112 (20q11.1). In each predicted fusion protein, the DNA-binding paired domain of PAX5 was present. Using quantitative PCR, we demonstrated that both the deletion and gene fusion events resulted in the same underexpression of PAX5, which extended to the differential expression of the PAX5 target genes, EBF1, ALDH1A1, ATP9A, and FLT3. Further molecular analysis showed deletion and mutation of the homologous PAX5 allele, providing further support for the key role of PAX5. Here, we show that specific gene loci may be the target of heterogeneous translocation breakpoints in human cancer, acting through a variety of mechanisms. This approach indicates an application for the identification of cancer genes in solid tumours, where unbalanced chromosomal rearrangements are particularly prevalent and few genes have been identified. It can be extrapolated that this strategy will reveal that the same mechanisms operate in cancer pathogenesis in general.

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More information

Published date: 4 November 2008
Organisations: Human Genetics, Cancer Sciences

Identifiers

Local EPrints ID: 69739
URI: https://eprints.soton.ac.uk/id/eprint/69739
ISSN: 0027-8424
PURE UUID: 30837d3a-59cf-4f93-91aa-3a02811fc5c2
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Jon C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

Catalogue record

Date deposited: 30 Nov 2009
Last modified: 06 Jun 2018 12:46

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