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.

  • Correspondence
  • Published:

Cryptic rearrangement involving MLL and AF10 occurring in utero

Leukemia volume 17, pages 1667–1669 (2003)Cite this article

TO THE EDITOR

Chimaeric fusion genes created by nonrandom chromosomal translocations are characteristic of childhood acute lymphoblastic (ALL) and myeloid (AML) leukaemias. Although the mechanisms leading to these chromosomal rearrangements are unclear, careful analysis of the primary genomic fusion sequence has suggested a number of possible mechanisms. These include, aberrant VDJ recombinase activity, topoisomerase II-mediated breakage followed by erroneous end joining, illegitimate recombination mediated by repetitive DNA sequences, proteins that bind to specific DNA-binding sites and errors in nonhomologous end joining (NHEJ) following double-stranded DNA breaks.1 Using polymerase chain reaction (PCR) -based techniques on DNA extracted from neonatal Guthrie cards, belonging to children diagnosed with leukaemia, it has been possible to show that some of these fusions occur prenatally. Fusions detected to date include the MLL-AF4 fusion in infantile ALL; the TEL-AML1 in childhood ALL and the AML1-ETO and MLL-CALM in childhood AML. Analysis of cells obtained from normal cord blood have shown that TEL-AML1 and AML1-ETO fusions are detected in the normal population at birth at a frequency that is a 100 times higher than the incidence of corresponding leukaemia.2 Thus, while the events leading to the formation of chimaeric fusion genes occur in utero, only a few develop clinically overt leukaemia at a later date in early childhood. This suggests that additional postnatal genetic hits are required in these preleukaemic cells. Murine models of TEL-AML1 and AML1-ETO support this hypothesis, as the transgenes are insufficient themselves to induce leukaemia. We extend these observations by identifying a child with AML carrying a prenatally acquired MLL-AF10 fusion.

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

Relevant articles

Open Access articles citing this article.

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
Figure 2

References

  1. Wechsler DS, Engstrom LD, Alexander BM, Motto DG, Roulston D . A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein. Genes Chromosomes Cancer 2003; 36: 26–36.

    Article  CAS  Google Scholar 

  2. Mori H, Colman SM, Xiao Z, Ford AM, Healy LE, Donaldson C et al. Chromosome translocations and covert leukemic clones are generated during normal fetal development. Proc Natl Acad Sci USA 2002; 99: 8242–8247.

    Article  CAS  Google Scholar 

  3. Beverloo HB, Le Coniat M, Wijsman J, Lillington DM, Bernard O, de Klein A et al. Breakpoint heterogeneity in t(10;11) translocation in AML-M4/M5 resulting in fusion of AF10 and MLL is resolved by fluorescent in situ hybridization analysis. Cancer Res 1995; 55: 4220–4224.

    CAS  PubMed  Google Scholar 

  4. Chaplin T, Jones L, Debernardi S, Hill AS, Lillington DM, Young BD . Molecular analysis of the genomic inversion and insertion of AF10 into MLL suggests a single-step event. Genes Chromosomes Cancer 2001; 30: 175–180.

    Article  CAS  Google Scholar 

  5. Chaplin T, Ayton P, Bernard OA, Saha V, Della Valle V, Hillion J et al. A novel class of zinc finger/leucine zipper genes identified from the molecular cloning of the t(10;11) translocation in acute leukemia. Blood 1995; 85: 1435–1441.

    CAS  Google Scholar 

  6. Chaplin T, Bernard O, Beverloo HB, Saha V, Hagemeijer A, Berger R et al. The t(10;11) translocation in acute myeloid leukemia (M5) consistently fuses the leucine zipper motif of AF10 onto the HRX gene. Blood 1995; 86: 2073–2076.

    CAS  PubMed  Google Scholar 

  7. Zhu C, Mills KD, Ferguson DO, Lee C, Manis J, Fleming J et al. Unrepaired DNA breaks in p53-deficient cells lead to oncogenic gene amplification subsequent to translocations. Cell 2002; 109: 811–821.

    Article  CAS  Google Scholar 

  8. DiMartino JF, Ayton PM, Chen EH, Naftzger CC, Young BD, Cleary ML . The AF10 leucine zipper is required for leukemic transformation of myeloid progenitors by MLL-AF10. Blood 2002; 99: 3780–3785.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr Anthony Ford of The Leukaemia Research Fund Centre for Cell and Molecular Biology, Chester Beatty Laboratories for his technical advice on the Guthrie spot analysis. This work is supported in part by the Joint Research Board (FWvD).

Author information

Authors and Affiliations

  1. Cancer Research UK Children's Cancer Group, Queen Mary University of London, UK

    L K Jones, F W van Delft, M Adamaki, S J Stoneham, N Patel & V Saha

  2. Medical Oncology Unit, Queen Mary University of London, UK

    M J Neat

  3. Cancer Research UK Computational Genome Analysis Laboratory, 44, Lincoln's Inn Fields, London, UK

    M P Mitchell

Authors
  1. L K Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M J Neat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F W van Delft
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M P Mitchell
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Adamaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S J Stoneham
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. V Saha
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jones, L., Neat, M., van Delft, F. et al. Cryptic rearrangement involving MLL and AF10 occurring in utero. Leukemia 17, 1667–1669 (2003). https://doi.org/10.1038/sj.leu.2403039

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403039

This article is cited by

Search

Advanced search

Quick links