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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.

Author information

1
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
2
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
3
Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
4
Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
5
Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
6
Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.
7
Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
8
Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria.
9
Medical University of Vienna, Vienna, Austria.

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.

KEYWORDS:

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

PMID:
26462019
PMCID:
PMC4741957
DOI:
10.18632/oncotarget.5520
[Indexed for MEDLINE]
Free PMC Article

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