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

doi:10.1073/pnas.0602360103

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

*Leukaemia Research Cytogenetics Group, Cancer Sciences Division, University of Southampton, Southampton SO16 6YD, United Kingdom;
^§Cancer Research UK Children's Cancer Group and
^¶Medical Oncology Unit, Institute of Cancer, Queen Mary University of London, London E1 4NS, United Kingdom;
^‖NimbleGen Systems, Inc., Madison, WI 53711;
**Department of Haematology, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, United Kingdom; and
^††Computer Learning Research Centre, Royal Holloway, University of London, Egham, Surrey TW20 0EX, United Kingdom

Communicated by Janet D. Rowley, University of Chicago Medical Center, Chicago, IL, March 27, 2006
↵ ^†J.C.S., F.W.v.D., V.S., and C.J.H. contributed equally to this work. (received for review July 29, 2005)

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.

Footnotes

^‡To whom correspondence should be addressed. E-mail: jcs{at}soton.ac.uk
Author contributions: J.C.S., V.S., and C.J.H. designed research; J.C.S., F.W.v.D., H.M.R., H.W., O.Y., R.S., and M.R. performed research; R.S. and T.R. contributed new reagents/analytic tools; J.C.S., F.W.v.D., H.M.R., H.W., O.Y., R.S., T.B., M.R., V.S., B.D.Y., and C.J.H. analyzed data; and J.C.S., F.W.v.D., I.H., V.S., and C.J.H. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

ALL,

acute lymphoblastic leukemia;

AML,

acute myeloid leukemia;

aCGH,

array-based comparative genomic hybridization;

CRA,

common region of amplification;

CRD,

common region of deletion;

FDR,

false discovery rate.