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Analysis of a breakpoint cluster reveals insight into the mechanism of intrachromosomal amplification in a lymphoid malignancy

Analysis of a breakpoint cluster reveals insight into the mechanism of intrachromosomal amplification in a lymphoid malignancy
Analysis of a breakpoint cluster reveals insight into the mechanism of intrachromosomal amplification in a lymphoid malignancy
A distinct sub-group of B-cell precursor acute lymphoblastic leukemia, defined by intrachromosomal amplification of chromosome 21 (iAMP21), is restricted to older children and has been associated with a poor outcome. Accurate diagnosis is important for appropriate risk stratification for treatment. It could be improved by understanding the initiating mechanism. iAMP21 is characterized by amplification of a 5.1-24 Mb region of chromosome 21, which includes the RUNX1 gene. It is thought to arise through a breakage-fusion-bridge (BFB) mechanism. Breakpoints initiating BFB cycles were determined from recent array data from 18 patients. Three occurred within the PDE9A gene. Other patients with breakpoints in PDE9A were identified by fluorescence in situ hybridization and molecular copy number counting. Sequencing defined a 1.7 Kb breakpoint cluster region, positioned 400 bp distal to an extensive region enriched for CA repeats with the potential to form Z-DNA. None of the rearranged sequences showed the inverted repeat structure characteristic of BFB; instead PDE9A was fused to intergenic regions of chromosome 21 or to genes on other chromosomes. These observations indicated that previously unrecognized complex events, involving microhomology-mediated end joining, preceded or accompanied initiation of the BFB cycle. A chi-like heptomer, CCTCAGC, contained four of the breakpoints, two within PDE9A and two within partner Alu-repeat sequences. This heptomer was closely homologous to a breakpoint hotspot within the TCF3 gene, suggesting involvement of a common novel recombinogenic mechanism that might also contribute to the recombinogenic potential of Alu repeats. These findings provide insight into potential mechanisms involved in the formation of iAMP21.
2591-2602
Sinclair, Paul B.
6453ef9d-248b-415a-8172-d693185689c8
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
An, Qian
6766de29-63b7-45eb-b21a-04cac9921373
Rand, Vikki
e61c839d-fda5-49e9-a497-e58bfad17934
Ensor, Hannah
f8f9956c-cb52-4b24-b3ae-ec42a383ce32
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Strefford, Jonathan C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
Sinclair, Paul B.
6453ef9d-248b-415a-8172-d693185689c8
Parker, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
An, Qian
6766de29-63b7-45eb-b21a-04cac9921373
Rand, Vikki
e61c839d-fda5-49e9-a497-e58bfad17934
Ensor, Hannah
f8f9956c-cb52-4b24-b3ae-ec42a383ce32
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Strefford, Jonathan C.
3782b392-f080-42bf-bdca-8aa5d6ca532f

Sinclair, Paul B., Parker, Helen, An, Qian, Rand, Vikki, Ensor, Hannah, Harrison, Christine J. and Strefford, Jonathan C. (2011) Analysis of a breakpoint cluster reveals insight into the mechanism of intrachromosomal amplification in a lymphoid malignancy. Human Molecular Genetics, 20 (13), 2591-2602. (doi:10.1093/hmg/ddr159). (PMID:21487021)

Record type: Article

Abstract

A distinct sub-group of B-cell precursor acute lymphoblastic leukemia, defined by intrachromosomal amplification of chromosome 21 (iAMP21), is restricted to older children and has been associated with a poor outcome. Accurate diagnosis is important for appropriate risk stratification for treatment. It could be improved by understanding the initiating mechanism. iAMP21 is characterized by amplification of a 5.1-24 Mb region of chromosome 21, which includes the RUNX1 gene. It is thought to arise through a breakage-fusion-bridge (BFB) mechanism. Breakpoints initiating BFB cycles were determined from recent array data from 18 patients. Three occurred within the PDE9A gene. Other patients with breakpoints in PDE9A were identified by fluorescence in situ hybridization and molecular copy number counting. Sequencing defined a 1.7 Kb breakpoint cluster region, positioned 400 bp distal to an extensive region enriched for CA repeats with the potential to form Z-DNA. None of the rearranged sequences showed the inverted repeat structure characteristic of BFB; instead PDE9A was fused to intergenic regions of chromosome 21 or to genes on other chromosomes. These observations indicated that previously unrecognized complex events, involving microhomology-mediated end joining, preceded or accompanied initiation of the BFB cycle. A chi-like heptomer, CCTCAGC, contained four of the breakpoints, two within PDE9A and two within partner Alu-repeat sequences. This heptomer was closely homologous to a breakpoint hotspot within the TCF3 gene, suggesting involvement of a common novel recombinogenic mechanism that might also contribute to the recombinogenic potential of Alu repeats. These findings provide insight into potential mechanisms involved in the formation of iAMP21.

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Published date: 1 July 2011

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Local EPrints ID: 192021
URI: http://eprints.soton.ac.uk/id/eprint/192021
PURE UUID: 946b8223-6c1b-4912-a310-c85fc9c826e8
ORCID for Helen Parker: ORCID iD orcid.org/0000-0001-8308-9781
ORCID for Jonathan C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881

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Date deposited: 29 Jun 2011 07:54
Last modified: 15 Mar 2024 03:20

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Contributors

Author: Paul B. Sinclair
Author: Helen Parker ORCID iD
Author: Qian An
Author: Vikki Rand
Author: Hannah Ensor
Author: Christine J. Harrison

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