Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Cytogenetics and Molecular Genetics

Identification of cryptic aberrations and characterization of translocation breakpoints using array CGH in high hyperdiploid childhood acute lymphoblastic leukemia

Leukemia volume 20, pages 2002–2007 (2006)Cite this article

Abstract

High hyperdiploidy, characterized by non-random trisomies, is the largest cytogenetic subgroup in childhood acute lymphoblastic leukemia (ALL). It is not known whether the gained chromosomes are sufficient for leukemogenesis or if additional genetic aberrations are necessary. However, the suboptimal chromosome morphology of hyperdiploid ALLs makes detection of structural abnormalities difficult if using cytogenetic techniques; alternative methods are, therefore, needed. We performed array comparative genome hybridization (CGH) analyses, with a resolution of 100 kb, of eight cases of high hyperdiploid childhood ALL to characterize structural abnormalities found with G-banding/multicolor fluorescence in situ hybridization (FISH) and to detect novel changes. The non-centromeric breakpoints of four rearrangements, including three translocations and one 1q duplication, were narrowed down to <0.2 Mb. Furthermore, four submicroscopic imbalances involving 0.6–2.7 Mb were detected, comprising two segmental duplications involving 1q22 and 12q24.31 in one case and two hemizygous deletions in 12p13.2–31 – including ETV6 – and in 13q32.3–33.1 in another case. Notably, FISH analysis of the latter revealed an associated reciprocal t(3;13)(q?;32.2–33.1). In conclusion, the array CGH analyses revealed putative leukemia-associated submicroscopic imbalances and rearrangements in 2/8 (25%) hyperdiploid ALLs. The detection and characterization of these additional genetic aberrations will most likely increase our understanding of the pathogenesis of high hyperdiploid childhood ALL.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Johansson B, Mertens F, Mitelman F . Clinical and biological importance of cytogenetic abnormalities in childhood and adult acute lymphoblastic leukemia. Ann Med 2004; 36: 492–503.

    Article  CAS  PubMed  Google Scholar 

  2. Moorman AV, Richards SM, Martineau M, Cheung KL, Robinson HM, Jalali GR et al. Outcome heterogeneity in childhood high-hyperdiploid acute lymphoblastic leukemia. Blood 2003; 102: 2756–2762.

    Article  CAS  PubMed  Google Scholar 

  3. Yeoh E-J, Ross ME, Shurtleff SA, Williams WK, Patel D, Mahfouz R et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell 2002; 1: 133–143.

    Article  CAS  PubMed  Google Scholar 

  4. Gruszka-Westwood AM, Horsley SW, Martinez-Ramirez A, Harrison CJ, Kempski H, Moorman AV et al. Comparative expressed sequence hybridization studies of high-hyperdiploid childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer 2004; 41: 191–202.

    Article  CAS  PubMed  Google Scholar 

  5. Andersson A, Olofsson T, Lindgren D, Nilsson B, Ritz C, Edén P et al. Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations. Proc Natl Acad Sci USA 2005; 102: 19069–19074.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yagi T, Hibi S, Tabata Y, Kuriyama K, Teramura T, Hashida T et al. Detection of clonotypic IGH and TCR rearrangements in the neonatal blood spots of infants and children with B-cell precursor acute lymphoblastic leukemia. Blood 2000; 96: 264–268.

    CAS  PubMed  Google Scholar 

  7. Panzer-Grümayer ER, Fasching K, Panzer S, Hettinger K, Schmitt K, Stöckler-Ipsiroglu S et al. Nondisjunction of chromosomes leading to hyperdiploid childhood B-cell precursor acute lymphoblastic leukemia is an early event during leukemogenesis. Blood 2002; 100: 347–349.

    Article  PubMed  Google Scholar 

  8. Taub JW, Konrad MA, Ge Y, Naber JM, Scott JS, Matherly LH et al. High frequency of leukemic clones in newborn screening blood samples of children with B-precursor acute lymphoblastic leukemia. Blood 2002; 99: 2992–2996.

    Article  CAS  PubMed  Google Scholar 

  9. Maia AT, van der Velden VHJ, Harrison CJ, Szczepanski T, Williams MD, Griffiths MJ et al. Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia 2003; 17: 2202–2206.

    Article  CAS  PubMed  Google Scholar 

  10. Maia AT, Tussiwand R, Cazzaniga G, Rebulla P, Colman S, Biondi A et al. Identification of preleukemic precursors of hyperdiploid acute lymphoblastic leukemia in cord blood. Genes Chromosomes Cancer 2004; 40: 38–43.

    Article  PubMed  Google Scholar 

  11. Onodera N, McCabe NR, Rubin CM . Formation of a hyperdiploid karyotype in childhood acute lymphoblastic leukemia. Blood 1992; 80: 203–208.

    CAS  PubMed  Google Scholar 

  12. Paulsson K, Panagopoulos I, Knuutila S, Jee KJ, Garwicz S, Fioretos T et al. Formation of trisomies and their parental origin in hyperdiploid childhood acute lymphoblastic leukemia. Blood 2003; 102: 3010–3015.

    Article  CAS  PubMed  Google Scholar 

  13. Paulsson K, Mörse H, Fioretos T, Behrendtz M, Strömbeck B, Johansson B . Evidence for a single-step mechanism in the origin of hyperdiploid childhood acute lymphoblastic leukemia. Genes Chromosomes Cancer 2005; 44: 113–122.

    Article  CAS  PubMed  Google Scholar 

  14. Armstrong SA, Mabon ME, Silverman LB, Li A, Gribben JG, Fox EA et al. FLT3 mutations in childhood acute lymphoblastic leukemia. Blood 2004; 103: 3544–3546.

    Article  CAS  PubMed  Google Scholar 

  15. Taketani T, Taki T, Sugita K, Furuichi Y, Ishii E, Hanada R et al. FLT3 mutations in the activation loop of tyrosine kinase domain are frequently found in infant ALL with MLL rearrangements and pediatric ALL with hyperdiploidy. Blood 2004; 103: 1085–1088.

    Article  CAS  PubMed  Google Scholar 

  16. Mitelman F, Johansson B, Mertens F . Mitelman Database of Chromosome Aberrations in Cancer 2006. http://cgap.nci.nih.gov/Chromosomes/Mitelman.

  17. Elghezal H, Le Guyader G, Radford-Weiss I, Perot C, Van Den Akker J, Eydoux P et al. Reassessment of childhood B-lineage lymphoblastic leukemia karyotypes using spectral analysis. Genes Chromosomes Cancer 2001; 30: 383–392.

    Article  CAS  PubMed  Google Scholar 

  18. Nordgren A, Farnebo F, Johansson B, Holmgren G, Forestier E, Larsson C et al. Identification of numerical and structural chromosome aberrations in 15 high hyperdiploid childhood acute lymphoblastic leukemias using spectral karyotyping. Eur J Haematol 2001; 66: 297–304.

    Article  CAS  PubMed  Google Scholar 

  19. Haas OA, Henn T, Romanakis K, du Manoir S, Lengauer C . Comparative genomic hybridization as part of a new diagnostic strategy in childhood hyperdiploid acute lymphoblastic leukemia. Leukemia 1998; 12: 474–481.

    Article  CAS  PubMed  Google Scholar 

  20. Kristensen TD, Wesenberg F, Jonsson OG, Carlsen NT, Forestier E, Kirchhoff M et al. High-resolution comparative genomic hybridisation yields a high detection rate of chromosomal aberrations in childhood acute lymphoblastic leukaemia. Eur J Haematol 2003; 70: 363–372.

    Article  CAS  PubMed  Google Scholar 

  21. Ishkanian AS, Malloff CA, Watson SK, deLeeuw RJ, Chi B, Coe BP et al. A tiling resolution DNA microarray with complete coverage of the human genome. Nat Genet 2004; 36: 299–303.

    Article  CAS  PubMed  Google Scholar 

  22. Krzywinski M, Bosdet I, Smailus D, Chiu R, Mathewson C, Wye N et al. A set of BAC clones spanning the human genome. Nucleic Acids Res 2004; 32: 3651–3660.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kolomietz E, Al-Maghrabi J, Brennan S, Karaskova J, Minkin S, Lipton J et al. Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis. Blood 2001; 97: 3581–3588.

    Article  CAS  PubMed  Google Scholar 

  24. ISCN. An International System for Human Cytogenetic Nomenclaturea, In: Shaffer LG, Tommerup N (eds). S Karger: Basel, 2005.

  25. Davidsson J, Paulsson K, Johansson B . Searching for cryptic chromosomal aberrations in high hyperdiploid childhood acute lymphoblastic leukemias. Eur J Haematol 2006; 76: 449–450.

    Article  PubMed  Google Scholar 

  26. Paulsson K, Heidenblad M, Strömbeck B, Staaf J, Jönsson G, Borg Å et al. High-resolution genome-wide array-based comparative genome hybridization reveals cryptic chromosome changes in AML and MDS cases with trisomy 8 as the sole cytogenetic aberration. Leukemia 2006; 20: 840–846.

    Article  CAS  PubMed  Google Scholar 

  27. Yang YH, Dudoit S, Luu P, Lin DM, Peng V, Ngai J et al. Normalization for cDNA microarray data: a robust composite method addressing single and multiple slide systematic variation. Nucleic Acids Res 2002; 30: e15.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Autio R, Hautaniemi S, Kauraniemi P, Yli-Harja O, Astola J, Wolf M et al. CGH-Plotter: MATLAB toolbox for CGH-data analysis. Bioinformatics 2003; 19: 1714–1715.

    Article  CAS  PubMed  Google Scholar 

  29. Saal LH, Troein C, Vallon-Christersson J, Gruvberger S, Borg Å, Peterson C . BioArray Software Environment (BASE): a platform for comprehensive management and analysis of microarray data. Genome Biol 2002; 3 software0003.

  30. Dyer MJS, Heward JM, Zani VJ, Buccheri V, Catovsky D . Unusual deletions within the immunoglobulin heavy-chain locus in acute leukemias. Blood 1993; 82: 865–871.

    CAS  PubMed  Google Scholar 

  31. Attarbaschi A, Mann G, König M, Dworzak MN, Trebo MM, Mühlegger N et al. Incidence and relevance of secondary chromosome abnormalities in childhood TEL/AML1+ acute lymphoblastic leukemia: an interphase FISH analysis. Leukemia 2004; 18: 1611–1616.

    Article  CAS  PubMed  Google Scholar 

  32. Martínez-Ramiréz A, Urioste M, Contra T, Cantalejo A, Tavares A, Portero JA et al. Fluorescence in situ hybridization study of TEL/AML1 fusion and other abnormalities involving TEL and AML1 genes. Correlation with cytogenetic findings and prognostic value in children with acute lymphocytic leukemia. Haematologica 2001; 86: 1245–1253.

    PubMed  Google Scholar 

  33. Harrison CJ, Moorman AV, Barber KE, Broadfield ZJ, Cheung KL, Harris RL et al. Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. Br J Haematol 2005; 129: 520–530.

    Article  PubMed  Google Scholar 

  34. Zhuang Z, Park W-S, Pack S, Schmidt L, Vortmeyer AO, Pak E et al. Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 1998; 20: 66–69.

    Article  CAS  PubMed  Google Scholar 

  35. Beghini A, Ripamonti CB, Castorina P, Pezzetti L, Doneda L, Cairoli R et al. Trisomy 4 leading to duplication of a mutated KIT allele in acute myeloid leukemia with mast cell involvement. Cancer Genet Cytogenet 2000; 119: 26–31.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Swedish Cancer Society, the Swedish Children's Cancer Foundation, and the Knut and Alice Wallenberg Foundation via the SWEGENE program.

Author information

Authors and Affiliations

  1. Department of Clinical Genetics, Lund University Hospital, Sweden

    K Paulsson, M Heidenblad, T Fioretos & B Johansson

  2. Department of Pediatrics, Lund University Hospital, Sweden

    H Mörse

  3. Department of Oncology, Lund University Hospital, Sweden

    Å Borg

  4. Lund Strategic Research Center for Stem Cell Biology and Cell Therapy, Lund University, Sweden

    Å Borg

Authors
  1. K Paulsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Heidenblad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H Mörse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Å Borg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. T Fioretos
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K Paulsson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Paulsson, K., Heidenblad, M., Mörse, H. et al. Identification of cryptic aberrations and characterization of translocation breakpoints using array CGH in high hyperdiploid childhood acute lymphoblastic leukemia. Leukemia 20, 2002–2007 (2006). https://doi.org/10.1038/sj.leu.2404372

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404372

Keywords

This article is cited by

Search

Advanced search

Quick links