title: ETV6/RUNX1 induces reactive oxygen species and drives the accumulation of DNA damage in B cells.
abstract: The t(12;21)(p13;q22) chromosomal translocation is the most frequent translocation in childhood B cell precursor-acute lymphoblastic leukemia and results in the expression of an ETV6/RUNX1 fusion protein. The frequency of ETV6/RUNX1 fusions in newborns clearly exceeds the leukemia rate revealing that additional events occur in ETV6/RUNX1-positive cells for leukemic transformation. Hitherto, the mechanisms triggering these second hits remain largely elusive. Thus, we generated a novel ETV6/RUNX1 transgenic mouse model where the expression of the fusion protein is restricted to CD19(+) B cells. These animals harbor regular B cell development and lack gross abnormalities. We established stable pro-B cell lines carrying the ETV6/RUNX1 transgene that allowed us to investigate whether ETV6/RUNX1 itself favors the acquisition of second hits. Remarkably, these pro-B cell lines as well as primary bone marrow cells derived from ETV6/RUNX1 transgenic animals display elevated levels of reactive oxygen species (ROS) as tested with ETV6/RUNX1 transgenic dihydroethidium staining. In line, intracellular phospho-histone H2AX flow cytometry and comet assay revealed increased DNA damage indicating that ETV6/RUNX1 expression enhances ROS. On the basis of our data, we propose the following model: the expression of ETV6/RUNX1 creates a preleukemic clone and leads to increased ROS levels. These elevated ROS favor the accumulation of secondary hits by increasing genetic instability and double-strand breaks, thus allowing preleukemic clones to develop into fully transformed leukemic cells.
authors: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors: Hans-Peter
authors: HP
authors: Kantner
authors: Wolfgang
authors: W
authors: Warsch
authors: Alessio
authors: A
authors: Delogu
authors: Eva
authors: E
authors: Bauer
authors: Harald
authors: H
authors: Esterbauer
authors: Emilio
authors: E
authors: Casanova
authors: Veronika
authors: V
authors: Sexl
authors: Dagmar
authors: D
authors: Stoiber
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism*; D004249:DNA Damage; D006801:Humans; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D018941:Antigens, CD19; D050676:Core Binding Factor Alpha 2 Subunit; D015514:Oncogene Proteins, Fusion; D017382:Reactive Oxygen Species; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein