title: The impact of TEL-AML1 (ETV6-RUNX1) expression in precursor B cells and implications for leukaemia using three different genome-wide screening methods.
abstract: The reciprocal translocation t(12;21)(p13;q22), the most common structural genomic alteration in B-cell precursor acute lymphoblastic leukaemia in children, results in a chimeric transcription factor TEL-AML1 (ETV6-RUNX1). We identified directly and indirectly regulated target genes utilizing an inducible TEL-AML1 system derived from the murine pro B-cell line BA/F3 and a monoclonal antibody directed against TEL-AML1. By integration of promoter binding identified with chromatin immunoprecipitation (ChIP)-on-chip, gene expression and protein output through microarray technology and stable labelling of amino acids in cell culture, we identified 217 directly and 118 indirectly regulated targets of the TEL-AML1 fusion protein. Directly, but not indirectly, regulated promoters were enriched in AML1-binding sites. The majority of promoter regions were specific for the fusion protein and not bound by native AML1 or TEL. Comparison with gene expression profiles from TEL-AML1-positive patients identified 56 concordantly misregulated genes with negative effects on proliferation and cellular transport mechanisms and positive effects on cellular migration, and stress responses including immunological responses. In summary, this work for the first time gives a comprehensive insight into how TEL-AML1 expression may directly and indirectly contribute to alter cells to become prone for leukemic transformation.
authors.affiliation: Heinrich-Heine University of Dusseldorf, Medical Faculty, Clinic for Pediatric Oncology, Hematology and Clinical Immunology, Dusseldorf, Germany.
authors.forename: Y
authors.initials: Y
authors.lastname: Linka
authors.forename: S
authors.initials: S
authors.lastname: Ginzel
authors.forename: M
authors.initials: M
authors.lastname: Krüger
authors.forename: A
authors.initials: A
authors.lastname: Novosel
authors.forename: M
authors.initials: M
authors.lastname: Gombert
authors.forename: E
authors.initials: E
authors.lastname: Kremmer
authors.forename: J
authors.initials: J
authors.lastname: Harbott
authors.forename: R
authors.initials: R
authors.lastname: Thiele
authors.forename: A
authors.initials: A
authors.lastname: Borkhardt
authors.forename: P
authors.initials: P
authors.lastname: Landgraf