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.
Highlights
Ewing sarcoma is a neoplasm of the bone and soft tissue
In order to confirm that EWS-FLI1 expression is induced in the E/F; Mx1-cre transgenic mouse model, protein and RNA was extracted from spleens of wt (C57BL/6) mice, E/F; control mice (E/F mice that did not inherit Mx1-cre), and pIpC induced E/F; Mx1-cre mice and were subjected to western blotting and RT-qPCR, respectively
The transgene was detected in the spleens of E/F; Mx1-cre mice verifying that the E/F; Mx1-cre transgenic mouse model expresses the therapeutic target of interest (Figures 1A and 1B)
Summary
Ewing sarcoma is a neoplasm of the bone and soft tissue. It is characterized by a pathognomonic chromosomal translocation involving EWS and FLI1 or related genes that occurs in about 95% of cases [1]. EWS is a member of TET family of RNA binding proteins that is ubiquitously expressed [2] with proposed functions in transcription [3, 4], RNA processing [5, 6], and signal transduction [7,8,9]. The translocation leads to juxtaposition of the amino-terminal portion of EWS with the carboxy-terminus of FLI1; the fusion protein differs from wild-type proteins based upon loss of the RNA binding domain of EWS and transactivational domain of FLI1 [11]. EWS-FLI1 fusion protein confers its tumorigenic phenotype through aberrant transcriptional activity [12,13,14,15] and splicing [16,17,18,19,20]
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