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Gewählte Publikation:

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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2015

AutorInnen: Minas, TZ; Han, J; Javaheri, T; Hong, SH; Schlederer, M; Saygideğer-Kont, Y; Çelik, H; Mueller, KM; Temel, I; Özdemirli, M; Kovar, H; Erkizan, HV; Toretsky, J; Kenner, L; Moriggl, R; Üren, A

Titel: YK-4-279 effectively antagonizes EWS-FLI1 induced leukemia in a transgenic mouse model.

Quelle: Oncotarget. 2015; 6(35):37678-37694



Autor/innen der Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard
Müller Kristina

Beteiligte Vetmed-Organisationseinheiten
Institut für Tierzucht und Genetik, Abteilung für Funktionelle Krebsgenomik
Institut für Pathologie, Abteilung für Labortierpathologie


Abstract:
Ewing sarcoma is an aggressive tumor of bone and soft tissue affecting predominantly children and young adults. Tumor-specific chromosomal translocations create EWS-FLI1 and similar aberrant ETS fusion proteins that drive sarcoma development in patients. ETS family fusion proteins and over-expressed ETS proteins are also found in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. Transgenic expression of EWS-FLI1 in mice promotes high penetrance erythroid leukemia with dense hepatic and splenic infiltrations. We identified a small molecule, YK-4-279, that directly binds to EWS-FLI1 and inhibits its oncogenic activity in Ewing sarcoma cell lines and xenograft mouse models. Herein, we tested in vivo therapeutic efficacy and potential side effects of YK-4-279 in the transgenic mouse model with EWS-FLI1 induced leukemia. A two-week course of treatment with YK-4-279 significantly reduced white blood cell count, nucleated erythroblasts in the peripheral blood, splenomegaly, and hepatomegaly of erythroleukemic mice. YK-4-279 inhibited EWS-FLI1 target gene expression in neoplastic cells. Treated animals showed significantly better overall survival compared to control mice that rapidly succumbed to leukemia. YK-4-279 treated mice did not show overt toxicity in liver, spleen, or bone marrow. In conclusion, this in vivo study highlights the efficacy of YK-4-279 to treat EWS-FLI1 expressing neoplasms and support its therapeutic potential for patients with Ewing sarcoma and other ETS-driven malignancies.


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