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. Highresolution 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

Genome complexity in acute lymphoblastic leukemia is revealed by array-based comparative genomic hybridization

“…The analysis of these patients contributed to the high frequency of chromosome 21 CNA. The majority of the remaining patients with chromosome 21 CNA belonged to a newly identified poor-risk cytogenetic sub-group in ALL (Harewood et al, 2003; Robinson et al, 2003), which we have defined as iAMP21 (Strefford et al, 2006). This study corroborated our earlier findings and confirmed the variable nature of this chromosomal abnormality.…”

Genome-wide profiling of genetic alterations in acute lymphoblastic leukemia: recent insights and future directions

“…22,23,[25][26][27][28][29][30][31][32][33][34][35]42 These studies have delineated regions of deletion (for example, ETV6 in B-ALL), have mapped translocation breakpoints, 25,30 have identified new CNA (for example, 9q34 duplication in T-ALL), 27 and characterized large and/or complex alterations (for example, gains of 1q and intrachromosomal amplification of chromosome 21 in B-ALL). 26,28 However, the superior resolution of oligonucleotide array platforms, such as SNP arrays, has enabled a more detailed and comprehensive characterization of genetic alterations in ALL.…”

“…Array-based comparative genomic hybridization (CGH) using bacterial artificial chromosomes (BACs) has been highly informative in many tumor types, including ALL. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] BAC arrays typically use probes derived from large (up to B200 kb) fragments of human genomic DNA cloned into BAC vectors. BAC arrays now offer tiling coverage of the majority of the human genome, and generally high signal-to-noise ratio, but due to the large probe size have limited ability to detect focal CNA, 36,37 which, as discussed below, are a hallmark of ALL.…”

Disruption of ETV6 in intron 2 results in upregulatory and insertional events in childhood acute lymphoblastic leukaemia

“…mRNA levels of TLX3, RANBP17, NPM1 and ETV6 were assessed using the Taqman gene Expression Assays (Applied Biosystems, Foster City, California, UK) in patient 3912 and in a series of controls according to standard methodologies. 46 The control samples included: normal bone marrow, two BCP-cell lines SEM, RCH-ACV and two T-ALL patients, cases 8956 and 11216 (negative controls) and HPB-ALL, a TLX3 overexpressing T-ALL cell line (positive control).…”