title: YK-4-279 effectively antagonizes EWS-FLI1 induced leukemia in a transgenic mouse model.
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.
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Tsion Zewdu
authors.initials: TZ
authors.lastname: Minas
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Han
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.
authors.forename: Tahereh
authors.initials: T
authors.lastname: Javaheri
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Sung-Hyeok
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schlederer
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Saygideğer-Kont
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Haydar
authors.initials: H
authors.lastname: Çelik
authors.affiliation: Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Mueller
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Idil
authors.initials: I
authors.lastname: Temel
authors.affiliation: Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Metin
authors.initials: M
authors.lastname: Özdemirli
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria.|Department of Pediatrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Kovar
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Hayriye Verda
authors.initials: HV
authors.lastname: Erkizan
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Toretsky
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.|Unit of Pathology of Laboratory Animals, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Kenner
authors.affiliation: Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria.|Medical University of Vienna, Vienna, Austria.|Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D007211:Indoles / Q000494:pharmacology*; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D015514:Oncogene Proteins, Fusion / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D051789:Proto-Oncogene Protein c-fli-1 / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics; D034802:RNA-Binding Protein EWS / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020349:Surface Plasmon Resonance
chemical_list: C106031:EWS-FLI fusion protein; D007211:Indoles; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D012333:RNA, Messenger; D034802:RNA-Binding Protein EWS; C562345:YK 4-279
keywords: ETS fusion proteins; EWS-FLI1; YK-4-279; erythoid leukemia; ewing sarcoma