ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells
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 tha...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-11-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558613800905 |
| _version_ | 1818915950524628992 |
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| author | Hans-Peter Kantner Wolfgang Warsch Alessio Delogu Eva Bauer Harald Esterbauer Emilio Casanova Veronika Sexl Dagmar Stoiber |
| author_facet | Hans-Peter Kantner Wolfgang Warsch Alessio Delogu Eva Bauer Harald Esterbauer Emilio Casanova Veronika Sexl Dagmar Stoiber |
| author_sort | Hans-Peter Kantner |
| collection | DOAJ |
| description | 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 doublestrand breaks, thus allowing preleukemic clones to develop into fully transformed leukemic cells. |
| first_indexed | 2024-12-20T00:10:25Z |
| format | Article |
| id | doaj.art-10ef1793a4d042bca5be089f008233ed |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-20T00:10:25Z |
| publishDate | 2013-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-10ef1793a4d042bca5be089f008233ed2022-12-21T20:00:31ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022013-11-0115111292130010.1593/neo.131310ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B CellsHans-Peter Kantner0Wolfgang Warsch1Alessio Delogu2Eva Bauer3Harald Esterbauer4Emilio Casanova5Veronika Sexl6Dagmar Stoiber7Ludwig Boltzmann Institute for Cancer Research, Vienna, AustriaInstitute of Pharmacology and Toxicology, Veterinary University of Vienna, Vienna, AustriaLudwig Boltzmann Institute for Cancer Research, Vienna, AustriaLudwig Boltzmann Institute for Cancer Research, Vienna, AustriaClinical Institute of Laboratory Medicine, Medical University of Vienna, Vienna, AustriaLudwig Boltzmann Institute for Cancer Research, Vienna, AustriaInstitute of Pharmacology and Toxicology, Veterinary University of Vienna, Vienna, AustriaLudwig Boltzmann Institute for Cancer Research, Vienna, AustriaThe 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 doublestrand breaks, thus allowing preleukemic clones to develop into fully transformed leukemic cells.http://www.sciencedirect.com/science/article/pii/S1476558613800905 |
| spellingShingle | Hans-Peter Kantner Wolfgang Warsch Alessio Delogu Eva Bauer Harald Esterbauer Emilio Casanova Veronika Sexl Dagmar Stoiber ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells Neoplasia: An International Journal for Oncology Research |
| title | ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells |
| title_full | ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells |
| title_fullStr | ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells |
| title_full_unstemmed | ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells |
| title_short | ETV6/RUNX1 Induces Reactive Oxygen Species and Drives the Accumulation of DNA Damage in B Cells |
| title_sort | etv6 runx1 induces reactive oxygen species and drives the accumulation of dna damage in b cells |
| url | http://www.sciencedirect.com/science/article/pii/S1476558613800905 |
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