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:

Mutant Wilms’ tumor 1 (WT1) mRNA with premature termination codons in acute myeloid leukemia (AML) is sensitive to nonsense-mediated RNA decay (NMD)

Leukemia volume 24, pages 660–663 (2010)Cite this article

The Wilms’ tumor 1 (WT1) gene on chromosome 11p13 encodes a Krupple-like zinc finger transcription factor that may act as a tumor suppressor or oncogene in leukemogenesis.1 Mutations in WT1 were initially identified in 10–15% of acute myeloid leukemia (AML) and 20% of biphenotypic leukemia.2 Recently, the frequency of 10–15% WT1 mutations in adult AML with normal karyotypes was confirmed using relatively large cohorts of AML patients.3, 4, 5, 6 In some studies WT1 mutations were implicated as an independent adverse prognostic marker for patients with normal karyotype AML (<60 years);2, 3, 4, 5 however, in other WT1 mutations did not have impact on outcome.6 Mutations in WT1 in AML often result in frame shifts introducing premature termination codons (PTC),2, 3, 4, 5 but it is not known whether WT1 mutant transcripts are degraded by the nonsense-mediated RNA decay (NMD) surveillance system.7

Here, we analyzed a cohort of 218 AML cases for WT1 mutations by RT-PCR for mutations in exons 6 to 9 (WT1-FOR3 5′-GAGAGCGATAACCACACAAC-3′ (exon6) and WT1-REV4 5′-CTGTATGAGTCCTGGTGTGGG-3′ (exon9) (bp1214–1619 (NM_024426)) followed by denaturing high performance liquid chromatography (dHPLC, sensitivity 10–20% (mutation dosage)) and sequencing. In six AML cases missense and in-frame insertion mutations were detectable in WT1 (no. 1–6, Table 1). These WT1 missense and in-frame mutants are expressed, because these transcripts were readily detectable by RT-PCR. Analyses of a diagnostic and relapse sample of AML case no. 2270 (no. 7, Table 1), carrying a double mutation, showed that the out-of-frame WT1 mutations were not present on a single allele and both present at relapse. Thus, the insertions of 11 bp and 1 bp do not result in the expression of a WT1 protein with an internal frame-shift, but encode truncated WT1 proteins from two alleles.

Table 1 WT1 mutations in 26 primary AML cases
Full size table

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

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Yang L, Han Y, Suarez Saiz F, Minden MD . A tumor suppressor and oncogene: the WT1 story. Leukemia 2007; 21: 868–876.

    Article  CAS  Google Scholar 

  2. King-Underwood L, Pritchard-Jones K . Wilms′ tumor (WT1) gene mutations occur mainly in acute myeloid leukemia and may confer drug resistance. Blood 1998; 91: 2961–2968.

    CAS  Google Scholar 

  3. Summers K, Stevens J, Kakkas I, Smith M, Smith LL, Macdougall F et al. Wilms’ tumour 1 mutations are associated with FLT3-ITD and failure of standard induction chemotherapy in patients with normal karyotype AML. Leukemia 2007; 21: 550–551.

    Article  CAS  Google Scholar 

  4. Paschka P, Marcucci G, Ruppert AS, Whitman SP, Mrozek K, Maharry K et al. Wilms tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: A Cancer and Leukemia Group B Study. J Clin Oncol 2008; 26: 4595–4602.

    Article  CAS  Google Scholar 

  5. Virappane P, Gale R, Hills R, Kakkas I, Summers K, Stevens J et al. Mutation of the Wilms tumor 1 gene is a poor prognostic factor associated with chemotherapy resistance in normal karyotype acute myeloid leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party. J Clin Oncol 2008; 26: 5429–5435.

    Article  CAS  Google Scholar 

  6. Gaidzik VI, Schlenk RF, Moschny S, Becker A, Bullinger L, Corbacioglu A et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia (AML): A Study of the German-Austrian AML Study Group (AMLSG). Blood 2009; 113: 4505–4511.

    Article  CAS  Google Scholar 

  7. Kuzmiak HA, Maquat LE . Applying nonsense-mediated mRNA decay research to the clinic: progress and challenges. Trends Mol Med 2006; 12: 306–316.

    Article  CAS  Google Scholar 

  8. Wouters BJ, Jorda MA, Keeshan K, Louwers I, Erpelinck-Verschueren CA, Tielemans D et al. Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1. Blood 2007; 110: 3706–3714.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported by grants from the Dutch Cancer Society (Koningin Wilhelmina Fonds)

Author information

Authors and Affiliations

  1. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands

    S Abbas, C A J Erpelinck-Verschueren, C S Goudswaard, B Löwenberg & P J M Valk

Authors
  1. S Abbas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C A J Erpelinck-Verschueren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C S Goudswaard
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B Löwenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. P J M Valk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P J M Valk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Abbas, S., Erpelinck-Verschueren, C., Goudswaard, C. et al. Mutant Wilms’ tumor 1 (WT1) mRNA with premature termination codons in acute myeloid leukemia (AML) is sensitive to nonsense-mediated RNA decay (NMD). Leukemia 24, 660–663 (2010). https://doi.org/10.1038/leu.2009.265

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.265

Search

Advanced search

Quick links