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Identification of RUNX1/AML1 as a classical tumor suppressor gene

Oncogene volume 22, pages 538–547 (2003)Cite this article

Abstract

Based on our previous results indicating the presence of a tumor suppressor gene (TSG), chromosome 21 was analysed for loss of heterozygosity (LOH) in 18 patients with acute myeloid leukemia (17, AML-M0; one, AML-M1). Allelotyping at polymorphic loci was performed on purified material, allowing unequivocal detection of allelic loss and homozygous deletions. Six AML-M0 patients shared a common region of LOH harboring a single gene: RUNX1 (AML1), the most frequent site of translocations in acute leukemia and a well-known fusion oncogene. Fluorescence in situ hybridization allowed the identification of deletions with breakpoints within RUNX1 in two patients as the cause of LOH. In the four others the LOH pattern and the presence of two karyotypically normal chromosomes 21 were in line with mitotic recombination. Further molecular and cytogenetic analyses showed that this caused homozygosity of primary RUNX1 mutations: two point mutations, a partial deletion and, most significantly, a complete deletion of RUNX1. These findings identify RUNX1 as a classical TSG: both alleles are mutated or absent in cancer cells from four of the 17 AML-M0 patients examined. In contrast to AML-M0, the AML-M1 patient was trisomic for chromosome 21 and has two mutated and one normal RUNX1 allele, suggesting that the order of mutagenic events leading to leukemia may influence the predominant tumor type.

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Acknowledgements

We thank H Vrieling, P Devilee and LG Fradkin for discussions and critical review of this manuscript; RAThW Gouw and KHG Kroeze-Jansema (Department of Human Genetics) for technical assistance, R van der Linden and M van der Keur (Department of Hematology) for cell sorting and G de Groot-Swings (Department of Hematology) for her help with the collection of cells. This work was supported by the Inter University Institute for Radio Pathology and Radiation Protection (IRS), and by the grants from the Calouste Gulbenkian Foundation and the Foundation for Science and Technology (Portugal) to FPG Silva.

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Author notes

  1. Hanneke C Kluin-Nelemans

    Present address: Department of Hematology, University Hospital Groningen, PO Box 30.001, 9700RG, Groningen, The Netherlands

Authors and Affiliations

  1. Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, P.O. Box 9503, Leiden, 2300RA, The Netherlands

    Fernando P G Silva, Bruno Morolli & Micheline Giphart-Gassler

  2. Department of Genetics, University of Bari, via Amendola 175/A, Bari, 70126, Italy

    Clelia T Storlazzi & Luisa Anelli

  3. Department of Clinical Cytogenetics, Leiden University Medical Center, P.O. Box 9503, Leiden, 2300RA, The Netherlands

    Hans Wessels

  4. Department of Molecular Cell Biology, Leiden University Medical Center, P.O. Box 9503, Leiden, 2300RA, The Netherlands

    Vladimir Bezrookove

  5. Department of Hematology, Leiden University Medical Center, P.O. Box 9503, Leiden, 2300RA, The Netherlands

    Hanneke C Kluin-Nelemans

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  1. Fernando P G Silva
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Correspondence to Micheline Giphart-Gassler.

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Silva, F., Morolli, B., Storlazzi, C. et al. Identification of RUNX1/AML1 as a classical tumor suppressor gene. Oncogene 22, 538–547 (2003). https://doi.org/10.1038/sj.onc.1206141

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