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Complex genomic alterations and gene expression in patients with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21

Complex genomic alterations and gene expression in patients with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21
Complex genomic alterations and gene expression in patients with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21
We have previously identified a unique subtype of acute lymphoblastic leukemia (ALL) associated with a poor outcome and characterized by intrachromosomal amplification of chromosome 21 including the RUNX1 gene (iAMP21). In this study, array-based comparative genomic hybridization (aCGH) (n = 10) detected a common region of amplification (CRA) between 33.192 and 39.796 Mb and a common region of deletion (CRD) between 43.7 and 47 Mb in 100% and 70% of iAMP21 patients, respectively. High-resolution genotypic analysis (n = 3) identified allelic imbalances in the CRA. Supervised gene expression analysis showed a distinct signature for eight patients with iAMP21, with 10% of overexpressed genes located within the CRA. The mean expression of these genes was significantly higher in iAMP21 when compared to other ALL samples (n = 45). Although genomic copy number correlated with overall gene expression levels within areas of loss or gain, there was considerable individual variation. A unique subset of differentially expressed genes, outside the CRA and CRD, were identified when gene expression signatures of iAMP21 were compared to ALL samples with ETV6-RUNX1 fusion (n = 21) or high hyperdiploidy with additional chromosomes 21 (n = 23). From this analysis, LGMN was shown to be overexpressed in patients with iAMP21 (P = 0.0012). Genomic and expression data has further characterized this ALL subtype, demonstrating high levels of 21q instability in these patients leading to proposals for mechanisms underlying this clinical phenotype and plausible alternative treatments.
array CGH, expression profiling, RUNX1, iAMP21, genomic instability
0027-8424
8167-8172
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
van Delft, Frederick W.
75df8e65-f9f9-4b8d-9ce3-980eefffe5a3
Robinson, Hazel M.
c406aa02-ca17-4ba1-9aa4-24bab6415fc0
Worley, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Yiannikouris, Olga
38159634-a123-4ab1-b4fb-021e5147cb8c
Selzer, Rebecca
c5a4bbe0-8fdd-4d8f-a0cf-e0bebfbf41b8
Richmond, Todd
d79c112f-eaa4-4d04-b9e3-139d9caaeeb5
Hann, Ian
acc48ebf-86d1-4ce5-a384-4f628d5d9031
Bellotti, Tony
6cde6497-8084-46b0-8edc-a5d6904ded49
Raghavan, Manoj
f8141a72-8c17-4da2-b193-e42e978cbc4a
Young, Bryan D.
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Saha, Vaskar
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Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e
Strefford, Jon C.
3782b392-f080-42bf-bdca-8aa5d6ca532f
van Delft, Frederick W.
75df8e65-f9f9-4b8d-9ce3-980eefffe5a3
Robinson, Hazel M.
c406aa02-ca17-4ba1-9aa4-24bab6415fc0
Worley, Helen
33e0cd81-d45f-49bc-9539-09345d79d895
Yiannikouris, Olga
38159634-a123-4ab1-b4fb-021e5147cb8c
Selzer, Rebecca
c5a4bbe0-8fdd-4d8f-a0cf-e0bebfbf41b8
Richmond, Todd
d79c112f-eaa4-4d04-b9e3-139d9caaeeb5
Hann, Ian
acc48ebf-86d1-4ce5-a384-4f628d5d9031
Bellotti, Tony
6cde6497-8084-46b0-8edc-a5d6904ded49
Raghavan, Manoj
f8141a72-8c17-4da2-b193-e42e978cbc4a
Young, Bryan D.
d6d3ff53-6b73-42e7-8d41-19d1f16c58d2
Saha, Vaskar
504b1363-24e3-4a07-ad46-b154f27cb7b6
Harrison, Christine J.
52da7673-509c-4b88-b92e-0c021c9c7d3e

Strefford, Jon C., van Delft, Frederick W., Robinson, Hazel M., Worley, Helen, Yiannikouris, Olga, Selzer, Rebecca, Richmond, Todd, Hann, Ian, Bellotti, Tony, Raghavan, Manoj, Young, Bryan D., Saha, Vaskar and Harrison, Christine J. (2006) Complex genomic alterations and gene expression in patients with acute lymphoblastic leukemia and intrachromosomal amplification of chromosome 21. Proceedings of the National Academy of Sciences, 103 (21), 8167-8172. (doi:10.1073/pnas.0602360103).

Record type: Article

Abstract

We have previously identified a unique subtype of acute lymphoblastic leukemia (ALL) associated with a poor outcome and characterized by intrachromosomal amplification of chromosome 21 including the RUNX1 gene (iAMP21). In this study, array-based comparative genomic hybridization (aCGH) (n = 10) detected a common region of amplification (CRA) between 33.192 and 39.796 Mb and a common region of deletion (CRD) between 43.7 and 47 Mb in 100% and 70% of iAMP21 patients, respectively. High-resolution genotypic analysis (n = 3) identified allelic imbalances in the CRA. Supervised gene expression analysis showed a distinct signature for eight patients with iAMP21, with 10% of overexpressed genes located within the CRA. The mean expression of these genes was significantly higher in iAMP21 when compared to other ALL samples (n = 45). Although genomic copy number correlated with overall gene expression levels within areas of loss or gain, there was considerable individual variation. A unique subset of differentially expressed genes, outside the CRA and CRD, were identified when gene expression signatures of iAMP21 were compared to ALL samples with ETV6-RUNX1 fusion (n = 21) or high hyperdiploidy with additional chromosomes 21 (n = 23). From this analysis, LGMN was shown to be overexpressed in patients with iAMP21 (P = 0.0012). Genomic and expression data has further characterized this ALL subtype, demonstrating high levels of 21q instability in these patients leading to proposals for mechanisms underlying this clinical phenotype and plausible alternative treatments.

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Published date: 2006
Additional Information: Published online before print May 15, 2006
Keywords: array CGH, expression profiling, RUNX1, iAMP21, genomic instability
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 40673
URI: http://eprints.soton.ac.uk/id/eprint/40673
ISSN: 0027-8424
PURE UUID: 3f994a10-c537-4487-9ca6-602d374f42e5
ORCID for Jon C. Strefford: ORCID iD orcid.org/0000-0002-0972-2881
ORCID for Helen Worley: ORCID iD orcid.org/0000-0001-8308-9781

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Date deposited: 07 Jul 2006
Last modified: 03 Dec 2019 01:50

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Contributors

Author: Frederick W. van Delft
Author: Hazel M. Robinson
Author: Helen Worley ORCID iD
Author: Olga Yiannikouris
Author: Rebecca Selzer
Author: Todd Richmond
Author: Ian Hann
Author: Tony Bellotti
Author: Manoj Raghavan
Author: Bryan D. Young
Author: Vaskar Saha
Author: Christine J. Harrison

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