Originally published as JCO Early Release 10.1200/JCO.2008.16.0333 on June 30 2008

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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

Priya Virappane, Rosemary Gale, Robert Hills, Ioannis Kakkas, Karin Summers, Jane Stevens, Christopher Allen, Claire Green, Hilmar Quentmeier, Hans Drexler, Alan Burnett, David Linch, Dominique Bonnet, T. Andrew Lister, Jude Fitzgibbon

From the Centre for Medical Oncology, Barts and the London School of Medicine; Department of Haematology, University College London; Hematopoietic Stem Cell Laboratory, London Research Institute, London; Department of Haematology, School of Medicine, Cardiff University, Cardiff, United Kingdom; Department of Immunology and Histocompatibility, Evangelismos General Hospital, Athens, Greece; and the DSMZ, Braunschweig, Germany

Corresponding author: Jude Fitzgibbon, PhD, Centre for Medical Oncology, Institute of Cancer, Barts and the London School of Medicine, Charterhouse Square, London EC1M 6BQ, United Kingdom; e-mail: jude.fitzgibbon{at}cancer.org.uk

Purpose To determine the clinical relevance of Wilms’ tumor 1 (WT1) gene mutations in acute myeloid leukemia (AML) with normal karyotype (NK).

Patients and Methods Exons 7 and 9 of WT1 were screened in samples from 470 young adult NK AMLs using a combination of direct sequencing and high-resolution capillary electrophoresis.

Results Overall, 51 mutations were detected in 47 cases (10%): 46 frameshift mutations with insertion/deletion of one to 28 base pairs in exon 7 (n = 45) or exon 9 (n = 1), with a median mutant level of 45% (range, 8% to 86%), and five substitutions in exon 9: D396N (n = 3), H397Y (n = 1) and H397Q (n = 1). Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases (complete remission rate, 79% v 90%, odds ratio [OR] = 3.02; 95% CI, 1.17 to 7.82; P = .02), a higher rate of resistant disease (15% v 4%; OR = 9.33; 95% CI, 2.38 to 36.6; P = .001), an increased cumulative incidence of relapse (67% v 43%, hazard ratio [HR] = 3.02; 95% CI, 1.69 to 5.38; P = .0008), with a reduction in both relapse-free survival (22% v 44%; HR = 2.16; 95% CI, 1.32 to 3.55; P = .005) and overall survival (26% v 47%; HR = 1.91; 95% CI, 1.23 to 2.95; P = .007) at 5 years. In multivariate analysis, which included FLT3 internal tandem duplication and NPM1 mutation status, the presence of a WT1 mutation remained an independent adverse prognostic factor.

Conclusion WT1 mutations are a negative prognostic indicator in NK AML and may be suitable for the development of targeted therapy.

published online ahead of print at www.jco.org on June 30, 2008.

Supported in part by grants from Cancer Research UK, Medical Research Council, Leukaemia Research Fund, the Research Advisory Board of Barts and the London School of Medicine, and The Cancer Committee of Barts and the London NHS Trust.

Presented at the 49th Annual Meeting of the American Society of Hematology, December 8-11, 2007, Atlanta, GA.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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