title: Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21.
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.
authors.affiliation: Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton SO16 6YD, United Kingdom. jcs@soton.ac.uk
authors.forename: Jon C
authors.initials: JC
authors.lastname: Strefford
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Delft
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Robinson
authors.forename: Helen
authors.initials: H
authors.lastname: Worley
authors.forename: Olga
authors.initials: O
authors.lastname: Yiannikouris
authors.forename: Rebecca
authors.initials: R
authors.lastname: Selzer
authors.forename: Todd
authors.initials: T
authors.lastname: Richmond
authors.forename: Ian
authors.initials: I
authors.lastname: Hann
authors.forename: Tony
authors.initials: T
authors.lastname: Bellotti
authors.forename: Manoj
authors.initials: M
authors.lastname: Raghavan
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: Vaskar
authors.initials: V
authors.lastname: Saha
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D000483:Alleles; D002869:Chromosome Aberrations; D022202:Chromosomes, Artificial, Bacterial; D002891:Chromosomes, Human, Pair 21; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D016678:Genome; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*