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.

  • Letter to the Editor
  • Published:

Haploinsufficiency of the MLL and TOB2 genes in lymphoid malignancy

Leukemia volume 24, pages 649–652 (2010)Cite this article

There are many different mechanisms by which the promiscuous MLL gene, with a diversity of partners, can be converted into an oncogene. These include translocations, duplications, insertions and deletions all of which have been linked to HOX gene deregulation as the mediator of haematological malignancy.1 To date, 104 different MLL rearrangements have been identified of which 64 translocation partner genes have been characterized at the molecular level.2 In almost all reported cases, MLL and the partner gene lie in a 5′–3′ orientation allowing for transcription of the fusion product. We describe two cases of lymphoid malignancy, one an acute leukaemia of B-cell origin and the other a precursor-T leukaemia/lymphoma both of which showed fusion of the MLL and TOB2 genes in a tail–tail orientation. To the best of our knowledge this is the first description of recurrent involvement of the MLL gene in a rearrangement, which does not permit transcription. We discuss the implications of this finding for malignancy.

Patient 9878, a 14-month-old baby girl, presented with a history of lethargy and fever and a mass on the right side of her forehead. She had suffered from chronic ill health since birth. On physical examination generalized lymphodenopathy and hepatosplenomegaly were seen, whereas skin biopsy showed Langerhans Cell Histiocytosis (LCH). A diagnosis of common/pre-B acute lymphoblastic leukaemia (ALL) was made with a white blood cell count of 23.6 × 109/l. Therapy was commenced according to UK ALL 2003 Regimen A, which was changed to Regimen C on day 15 when she was discovered to have a rearrangement of the MLL gene. The patient entered remission but had a bone marrow relapse with refractory ALL 15 months after diagnosis. She was started on the UK ALL R3 protocol but relapsed again 2 months later. A third line of chemotherapy was abandoned for clinical reasons and in view of the poor prognosis cytogenetics. The patient died shortly afterwards.

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

References

  1. Daser A, Rabbitts TH . The versatile mixed lineage leukaemia gene MLL and its many associations in leukaemogenesis. Semin Cancer Biol 2005; 15: 175–188.

    Article  CAS  Google Scholar 

  2. Meyer C, Kowarz E, Hofmann J, Renneville A, Zuna J, Trka J et al. New insights to the MLL recombinome of acute leukemias. Leukemia 2009; 23: 1490–1499.

    Article  CAS  Google Scholar 

  3. Schraets D, Lehmann T, Dingermann T, Marschalek R . MLL-mediated transcriptional gene regulation investigated by gene expression profiling. Oncogene 2003; 22: 3655–3668.

    Article  CAS  Google Scholar 

  4. Cano F, Drynan LF, Pannell R, Rabbitts TH . Leukaemia lineage specification caused by cell-specific Mll-Enl translocations. Oncogene 2008; 27: 1945–1950.

    Article  CAS  Google Scholar 

  5. Teuffel O, Betts DR, Thali M, Eberle D, Meyer C, Schneider B et al. Clonal expansion of a new MLL rearrangement in the absence of leukemia. Blood 2005; 105: 4151–4152.

    Article  CAS  Google Scholar 

  6. Meyer C, Schneider B, Jakob S, Strehl S, Attarbaschi A, Schnittger S et al. The MLL recombinome of acute leukemias. Leukemia 2006; 20: 777–784.

    Article  CAS  Google Scholar 

  7. Feldman AL, Berthold F, Arceci RJ, Abramowsky C, Shehata BM, Mann KP et al. Clonal relationship between precursor T-lymphoblastic leukaemia/lymphoma and Langerhans-cell histiocytosis. Lancet Oncol 2005; 6: 435–437.

    Article  Google Scholar 

  8. Betts DR, Leibundgut KE, Feldges A, Pluss HJ, Niggli FK . Cytogenetic abnormalities in Langerhans cell histiocytosis. Br J Cancer 1998; 77: 552–555.

    Article  CAS  Google Scholar 

  9. Largaespada DA . Haploinsufficiency for tumor suppression: the hazards of being single and living a long time. J Exp Med 2001; 193: F15–F18.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Professor Terry Rabbitts for helpful discussion and Leukaemia Research for financial support.

Author information

Authors and Affiliations

  1. Cancer Sciences Division, University of Southampton, Southampton, UK

    Q An, Z Konn, A Stewart, J C Strefford & M Martineau

  2. Department of Paediatric Oncology and Haematology, Addenbrookes Hospital, Cambridge, UK

    G A A Burke & W Myooren

  3. Haematology Cytogenetics Laboratory, Section of Haemato-Oncology, Institute of Cancer Research, Sutton, Surrey, UK

    M Dainton

  4. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle, UK

    C J Harrison

  5. Paediatric Malignancy Unit, Molecular Haematology and Cancer Biology, Great Ormond Street Hospital, London, UK

    H Kempski & D Webb

  6. Paediatric Oncology, Royal Marsden Hospital, London, UK

    M Taj

Authors
  1. Q An
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G A A Burke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Dainton
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C J Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Kempski
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Z Konn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W Myooren
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. A Stewart
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Taj
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. D Webb
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J C Strefford
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. M Martineau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C J Harrison.

Rights and permissions

Reprints and permissions

About this article

Cite this article

An, Q., Burke, G., Dainton, M. et al. Haploinsufficiency of the MLL and TOB2 genes in lymphoid malignancy. Leukemia 24, 649–652 (2010). https://doi.org/10.1038/leu.2009.238

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.238

Search

Advanced search

Quick links