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Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia

Oncogene volume 24, pages 3678–3683 (2005)Cite this article

Abstract

Murine radiation-induced acute myeloid leukaemia (AML) is characterized by loss of one copy of chromosome 2. Previously, we positioned the critical haematopoietic-specific transcription factor PU.1 within a minimally deleted region. We now report a high frequency (>65%) of missense mutation at codon 235 in the DNA-binding Ets domain of PU.1 in murine AML. Earlier studies, outside the context of malignancy, determined that conversion of arginine 235 (R235) to any other amino-acid residue leads to ablation of DNA-binding function and loss of expression of downstream targets. We show that mutation of R235 does not lead to protein loss, and occurs specifically in those AMLs showing loss of one copy of PU.1 (P=0.001, Fisher's exact test). PU.1 mutations were not found in the coding region, UTRs or promoter of human therapy-related AMLs. Potentially regulatory elements upstream of PU.1 were located but no mutations found. In conclusion, we have identified the cause of murine radiation-induced AML and have shown that loss of one copy of PU.1, as a consequence of flanking radiation-sensitive fragile domains on chromosome 2, and subsequent R235 conversion are highly specific to this mouse model. Such a mechanism does not operate, or is extremely rare, in human AML.

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Acknowledgements

We acknowledge support by Cancer Research UK and EU under 4th and 5th framework programmes (contract numbers F14PLT-95-00089, FIGH-CT-1999-00006 and FIGH-CT-1999-00035).

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Authors and Affiliations

  1. Cancer Research UK Laboratories, St Mark's Hospital, Harrow, UK

    Nirosha Suraweera, Ian P M Tomlinson & Andrew Silver

  2. Nuclear Research and Consultancy Group, Petten, The Netherlands

    Emmy Meijne & Rene Huiskamp

  3. National Radiological Protection Board, Chilton, Didcot, UK

    John Moody

  4. Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London, UK

    Luis G Carvajal-Carmona, Patrick Pollard, Andrew Rowan & Ian P M Tomlinson

  5. Radiation Hazard Research Group, Radiation Safety Research Center, National Institute of Radiological Sciences, Chiba, Japan

    Kazuko Yoshida

  6. Cancer Research UK Medical Oncology Unit, St Bartholomew's Hospital, London, UK

    Jude Fitzgibbon

  7. Bute Medical School, University of St Andrew's, St Andrews, Scotland, UK

    Andrew Riches

  8. Department of Toxicogenetics, Leiden University Medical Center, The Netherlands

    Theo van Laar

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  1. Nirosha Suraweera
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  2. Emmy Meijne
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  3. John Moody
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  13. Andrew Silver
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Correspondence to Andrew Silver.

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Suraweera, N., Meijne, E., Moody, J. et al. Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia. Oncogene 24, 3678–3683 (2005). https://doi.org/10.1038/sj.onc.1208422

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