Complex Genomic Alterations and Gene Expression in Acute Lymphoblastic Leukemia with 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) det...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2006-05, Vol.103 (21), p.8167-8172
Main Authors: Strefford, Jon C., van Delft, Frederik W., Robinson, Hazel M., Worley, Helen, Yiannikouris, Olga, Selzer, Rebecca, Richmond, Todd, Hann, Ian, Bellotti, Tony, Raghavan, Manoj, Young, Bryan D., Saha, Vaskar, Harrison, Christine J.
Format: Article
Language:English
Subjects:
Alleles
Biological Sciences
Chromosome Aberrations
Chromosomes
Chromosomes, Artificial, Bacterial
Chromosomes, Human, Pair 21
Cytogenetics
Fluorescence in situ hybridization
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes
Genetic Predisposition to Disease
Genetic variation
Genome
Genome, Human
Genomics
Genotype
Genotype & phenotype
Humans
Hybridization
In Situ Hybridization, Fluorescence
Leukemia
Myeloid leukemia
Oligonucleotide Array Sequence Analysis
Oligonucleotides
Phenotype
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0602360103