title: Modeling the evolution of ETV6-RUNX1-induced B-cell precursor acute lymphoblastic leukemia in mice.
abstract: The t(12;21) translocation that generates the ETV6-RUNX1 (TEL-AML1) fusion gene, is the most common chromosomal rearrangement in childhood cancer and is exclusively associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The translocation arises in utero and is necessary but insufficient for the development of leukemia. Single-nucleotide polymorphism array analysis of ETV6-RUNX1 patient samples has identified multiple additional genetic alterations; however, the role of these lesions in leukemogenesis remains undetermined. Moreover, murine models of ETV6-RUNX1 ALL that faithfully recapitulate the human disease are lacking. To identify novel genes that cooperate with ETV6-RUNX1 in leukemogenesis, we generated a mouse model that uses the endogenous Etv6 locus to coexpress the Etv6-RUNX1 fusion and Sleeping Beauty transposase. An insertional mutagenesis screen was performed by intercrossing these mice with those carrying a Sleeping Beauty transposon array. In contrast to previous models, a substantial proportion (20%) of the offspring developed BCP-ALL. Isolation of the transposon insertion sites identified genes known to be associated with BCP-ALL, including Ebf1 and Epor, in addition to other novel candidates. This is the first mouse model of ETV6-RUNX1 to develop BCP-ALL and provides important insight into the cooperating genetic alterations in ETV6-RUNX1 leukemia.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK. lvdw@sanger.ac.uk
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.forename: George
authors.initials: G
authors.lastname: Giotopoulos
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.forename: Louise S
authors.initials: LS
authors.lastname: Matheson
authors.forename: Frederik W
authors.initials: FW
authors.lastname: van Delft
authors.forename: Jun
authors.initials: J
authors.lastname: Kong
authors.forename: Anne E
authors.initials: AE
authors.lastname: Corcoran
authors.forename: Mel F
authors.initials: MF
authors.lastname: Greaves
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Huntly
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002469:Cell Separation; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019895:Transposases / Q000235:genetics; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D019895:Transposases; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein