YK-4-279 effectively antagonizes EWS-FLI1 induced leukemia in a transgenic mouse model
| Autor: | Kristina M. Mueller, Heinrich Kovar, Metin Ozdemirli, Yasemin Saygideğer-Kont, Aykut Üren, Idil Temel, Tsion Z. Minas, Jeffrey A. Toretsky, Lukas Kenner, Tahereh Javaheri, Jenny Han, Haydar Çelik, Richard Moriggl, Michaela Schlederer, Sung-Hyeok Hong, Hayriye V. Erkizan |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Genetically modified mouse
Pathology medicine.medical_specialty Chromatin Immunoprecipitation Indoles Oncogene Proteins Fusion Blotting Western Spleen Mice Transgenic Real-Time Polymerase Chain Reaction Immunoenzyme Techniques Mice White blood cell medicine Animals Humans RNA Messenger EWS-FLI1 ETS fusion proteins YK-4-279 business.industry erythoid leukemia Proto-Oncogene Protein c-fli-1 Reverse Transcriptase Polymerase Chain Reaction Myeloid leukemia Surface Plasmon Resonance medicine.disease Flow Cytometry Fusion protein Gene Expression Regulation Neoplastic Leukemia Disease Models Animal medicine.anatomical_structure Oncology Bone marrow Sarcoma Leukemia Erythroblastic Acute RNA-Binding Protein EWS business ewing sarcoma Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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