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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Chromatin Immunoprecipitation
  • Disease Models, Animal*
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Humans
  • Immunoenzyme Techniques
  • Indoles / pharmacology*
  • Leukemia, Erythroblastic, Acute / drug therapy*
  • Leukemia, Erythroblastic, Acute / etiology*
  • Leukemia, Erythroblastic, Acute / pathology
  • Mice
  • Mice, Transgenic
  • Oncogene Proteins, Fusion / administration & dosage
  • Oncogene Proteins, Fusion / antagonists & inhibitors*
  • Oncogene Proteins, Fusion / toxicity*
  • Proto-Oncogene Protein c-fli-1 / administration & dosage
  • Proto-Oncogene Protein c-fli-1 / antagonists & inhibitors*
  • Proto-Oncogene Protein c-fli-1 / toxicity*
  • RNA, Messenger / genetics
  • RNA-Binding Protein EWS / administration & dosage
  • RNA-Binding Protein EWS / antagonists & inhibitors*
  • RNA-Binding Protein EWS / toxicity*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Surface Plasmon Resonance

Substances

  • EWS-FLI fusion protein
  • Indoles
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Protein c-fli-1
  • RNA, Messenger
  • RNA-Binding Protein EWS
  • YK 4-279