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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.

SUBMITTER: Kantner HP 

PROVIDER: S-EPMC3858895 | biostudies-other | 2013 Nov

REPOSITORIES: biostudies-other

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ETV6/RUNX1 induces reactive oxygen species and drives the accumulation of DNA damage in B cells.

Kantner Hans-Peter HP   Warsch Wolfgang W   Delogu Alessio A   Bauer Eva E   Esterbauer Harald H   Casanova Emilio E   Sexl Veronika V   Stoiber Dagmar D  

Neoplasia (New York, N.Y.) 20131101 11


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  ...[more]

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