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Oncotarget. 2015 Nov 10;6(35):37678-94. doi: 10.18632/oncotarget.5520.

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

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Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria.
Medical University of Vienna, Vienna, Austria.


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.


ETS fusion proteins; EWS-FLI1; YK-4-279; erythoid leukemia; ewing sarcoma

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