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Wilms' tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML

Leukemia volume 21, pages 550–551 (2007)Cite this article

Wilms' tumour 1 gene (WT1) is highly expressed in various types of leukaemia which has advanced its position both as a target for immunotherapy and as a means of monitoring minimal residual disease (MRD). The precise role of WT1 in haematopoiesis and its contribution to leukemogenesis are open to speculation.1 One hypothesis is that wild-type WT1 may act both as an enhancer of cellular quiescence in haematopoietic stem cells and later as an inducer of cellular differentiation in committed precursors.2 Hence, abrogation of WT1 function could promote stem cell proliferation and induce a block in differentiation, the hallmarks of the two-step hypothesis for the development of acute myeloid leukemia (AML). Mutations in WT1 occur in 10–15% of AMLs, and a link between mutation and failure to respond to standard induction chemotherapy has been proposed.3 In support of this study, Nyvold et al.4 noted the emergence of a WT1 - mutated subclone following therapy suggesting that mutation of WT1 could lead to progression of leukemia by conferring drug resistance. Our group recently reported an association between acquired uniparental disomy of 11p and homozygous mutation of WT1 in a patient with normal karyotype AML.5 As this patient was also refractory to first-line chemotherapy, we investigated the relationship between WT1 mutation and treatment outcome in patients with normal cytogenetics.

If these mutations overlap with primer and probe combinations, they have the potential to interfere with WT1 quantification and the calculation of MRD.4 Using the standard real-time quantitative reverse-transcriptase polymerase chain reaction conditions described by Nyvold et al., all six mutations described for exon 7, in our group of patients, will affect primer/probe annealing and are likely to lead to a reduction in overall WT1 quantification. Hence, the effect of WT1 mutation on MRD detection may prove important although it is only in the rare cases where biallelic mutation coincides with the location of the primer/probe that complete loss of expression will be observed.

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Acknowledgements

This work was supported by the Newman Foundation, Cancer Research UK and the Royal London Charitable Foundation. We would also like to thank Iram Gull and Victoria Miller for sample collection and storage, Susan Weiss for assistance in preparing the figures and Rifca le Dieu, Kajsa Paulson and David Taussig for helpful discussion on the manuscript.

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Authors and Affiliations

  1. Centre for Medical Oncology, Barts and the London School of Medicine and Dentistry, London, UK

    K Summers, J Stevens, I Kakkas, L L Smith, F MacDougall, B D Young, T A Lister & J Fitzgibbon

  2. Department of Hematology, Guy's Hospital, London, UK

    M Smith

  3. Department of Hematology, St Bartholomew's Hospital, London, UK

    J Cavenagh

  4. Haematopoietic Stem Cell Laboratory, Cancer Research UK, London Research Institute, London, UK

    D Bonnet

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  1. K Summers
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Correspondence to J Fitzgibbon.

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Summers, K., Stevens, J., Kakkas, I. et al. Wilms' tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 21, 550–551 (2007). https://doi.org/10.1038/sj.leu.2404514

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