title: Identification of RUNX1/AML1 as a classical tumor suppressor gene.
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.
authors.affiliation: Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center, P.O. Box 9503, 2300RA Leiden, The Netherlands.
authors.forename: Fernando P G
authors.initials: FP
authors.lastname: Silva
authors.forename: Bruno
authors.initials: B
authors.lastname: Morolli
authors.forename: Clelia T
authors.initials: CT
authors.lastname: Storlazzi
authors.forename: Luisa
authors.initials: L
authors.lastname: Anelli
authors.forename: Hans
authors.initials: H
authors.lastname: Wessels
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.forename: Hanneke C
authors.initials: HC
authors.lastname: Kluin-Nelemans
authors.forename: Micheline
authors.initials: M
authors.lastname: Giphart-Gassler
mesh_terms: D000208:Acute Disease; D002891:Chromosomes, Human, Pair 21; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics*; D005434:Flow Cytometry; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D007951:Leukemia, Myeloid / Q000235:genetics; D019656:Loss of Heterozygosity; D017354:Point Mutation; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C493728:RUNX1 protein, human; D014157:Transcription Factors