title: Somatic heterozygous mutations in ETV6 (TEL) and frequent absence of ETV6 protein in acute myeloid leukemia.
abstract: ETV6 (ets translocation variant gene 6) TEL (translocation ets leukemia), encoding a transcriptional repressor, is involved in various translocations associated with human malignancies. Strikingly, the nonrearranged ETV6 allele is often deleted or inactivated in cells harboring these translocations. Although ETV6 translocations are infrequent in acute myeloid leukemia (AML), mutations or deregulated expression of ETV6 may contribute to leukemogenesis. To investigate the involvement of ETV6 in AML, we analysed 300 newly diagnosed patients for mutations in the coding region of the gene. Furthermore, we studied protein expression in 77 patients using two ETV6-specific antibodies. Five somatic heterozygous mutations were detected, which affected either the homodimerization- or the DNA-binding domain of ETV6. The proteins translated from the cDNAs of these mutants were unable to repress transcription and showed dominant-negative effects. In addition, we demonstrate that one-third of AML patients have deficient ETV6 protein expression, which is not related to ETV6 mRNA expression levels. In conclusion, we demonstrate that ETV6 abnormalities are not restricted to translocations and occur more frequently in AML than previously thought. Additional comprehensive studies are required to define the clinical consequence of ETV6 loss of function in AML.
authors.affiliation: Department of Hematology, ErasmusMC, Dr Molewaterplein 50, Rotterdam 3015GE, The Netherlands.
authors.forename: Sahar
authors.initials: S
authors.lastname: Barjesteh van Waalwijk van Doorn-Khosrovani
authors.forename: Dominik
authors.initials: D
authors.lastname: Spensberger
authors.forename: Yvonne
authors.initials: Y
authors.lastname: de Knegt
authors.forename: Michelle
authors.initials: M
authors.lastname: Tang
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Ruud
authors.initials: R
authors.lastname: Delwel
mesh_terms: D000208:Acute Disease; D001854:Bone Marrow Cells / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D005787:Gene Frequency; D006579:Heterozygote; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins / Q000235:genetics*; D017384:Sequence Deletion; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein