YK-4-279 Effectively Antagonizes EWS-FLI1 Induced Leukemia in a Transgenic Mouse Model

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Oct 14

PMID 26462019

Citations 17

Authors

Tsion Zewdu Minas

Jenny Han

Tahereh Javaheri

Sung-Hyeok Hong

Michaela Schlederer

Yasemin Saygideger-Kont

Haydar Celik

Kristina M Mueller

Idil Temel

Metin Ozdemirli

Heinrich Kovar

Hayriye Verda Erkizan

Jeffrey Toretsky

Lukas Kenner

Richard Moriggl

Aykut Uren

Affiliations

Soon will be listed here.

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.

Citing Articles

Zooming in on Long Non-Coding RNAs in Ewing Sarcoma Pathogenesis.

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YK-4-279 Attenuates Progression of Pre-Existing Pigmented Lesions to Nodular Melanoma in a Mouse Model.

Huang L, Zhai Y, Fajardo C, Lang D Cancers (Basel). 2022; 14(1).

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Challenges in modeling EWS-FLI1-driven transgenic mouse model for Ewing sarcoma.

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