Oncotarget

Research Papers:

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

Tsion Zewdu Minas _, Jenny Han, Tahereh Javaheri, Sung-Hyeok Hong, Michaela Schlederer, Yasemin Saygideğer-Kont, Haydar Çelik, Kristina M. Mueller, Idil Temel, Metin Özdemirli, Heinrich Kovar, Hayriye Verda Erkizan, Jeffrey Toretsky, Lukas Kenner, Richard Moriggl and Aykut Üren

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Oncotarget. 2015; 6:37678-37694. https://doi.org/10.18632/oncotarget.5520

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Abstract

Tsion Zewdu Minas1,*, Jenny Han1,*, Tahereh Javaheri3, Sung-Hyeok Hong1, Michaela Schlederer3,4, Yasemin Saygideğer-Kont1, Haydar Çelik1, Kristina M. Mueller8, Idil Temel1, Metin Özdemirli2, Heinrich Kovar7,9, Hayriye Verda Erkizan1, Jeffrey Toretsky1, Lukas Kenner3,4,5, Richard Moriggl3,6,8, Aykut Üren1

1Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

2Department of Pathology, Georgetown University Medical Center, Washington, DC, USA

3Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria

4Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria

5Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria

6Medical University of Vienna, Vienna, Austria

7Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria

8Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria

9Department of Pediatrics, Medical University of Vienna, Vienna, Austria

*These authors have contributed equally to this work

Correspondence to:

Aykut Üren, e-mail: au26@georgetown.edu

Keywords: EWS-FLI1, ETS fusion proteins, YK-4-279, ewing sarcoma, erythoid leukemia

Received: June 11, 2015     Accepted: September 28, 2015     Published: October 08, 2015

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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