YK-4-279 effectively antagonizes EWS-FLI1 induced leukemia in a transgenic mouse model
ONCOTARGET, cilt.6, sa.35, ss.37678-37694, 2015 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 6 Sayı: 35
- Basım Tarihi: 2015
- Doi Numarası: 10.18632/oncotarget.5520
- Dergi Adı: ONCOTARGET
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Sayfa Sayıları: ss.37678-37694
- Anahtar Kelimeler: EWS-FLI1, ETS fusion proteins, YK-4-279, ewing sarcoma, erythoid leukemia, TERT PROMOTER MUTATIONS, HUMAN MYELOID-LEUKEMIA, RNA-POLYMERASE-II, TRANSCRIPTION FACTOR, EWINGS-SARCOMA, FUSION PROTEIN, NEUROECTODERMAL TUMOR, GENE, DOMAIN, ERG
- Çukurova Üniversitesi Adresli: Hayır
Özet
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.