Research Papers:
YK4279 effectively antagonizes EWSFLI1 induced leukemia in a transgenic mouse model
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Tsion Zewdu Minas1,*, Jenny Han1,*, Tahereh Javaheri3, Sung-Hyeok Hong1, Michaela Schlederer3,4, Yasemin SaygideÄŸer-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: [email protected]
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.