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Novel flavagline‐like compounds with potent Fli‐1 inhibitory activity suppress diverse types of leukemia
Author(s) -
Song Jialei,
Yuan Chunmao,
Yang Jue,
Liu Tangjingjun,
Yao Yao,
Xiao Xiao,
Gajendran Babu,
Xu Dahai,
Li YouJun,
Wang Chunlin,
Liu Wuling,
Wen Min,
Spaner David,
Filmus Jorge,
Zacksenhaus Eldad,
Zhang Yiguo,
Hao Xiaojiang,
BenDavid Yaacov
Publication year - 2018
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14690
Subject(s) - transactivation , transcription factor , cancer research , mapk/erk pathway , biology , leukemia , ets transcription factor family , gene , kinase , microbiology and biotechnology , genetics
E26 transformation‐specific ( ETS ) gene family contains a common DNA ‐binding domain, the ETS domain, responsible for sequence‐specific DNA recognition on target promoters. The Fli‐1 oncogene, a member of ETS gene family, plays a critical role in hematopoiesis and is overexpressed in diverse hematological malignancies. This ETS transcription factor regulates genes controlling several hallmarks of cancer and thus represents an excellent target for cancer therapy. By screening compounds isolated from the medicinal plant Dysoxylum binectariferum in China, we identified two chemically related flavagline‐like compounds including 4′‐demethoxy‐3′,4′‐methylenedioxyrocaglaol and rocaglaol that strongly inhibited Fli‐1 transactivation ability. These compounds altered expression of Fli‐1 target genes including GATA 1, EKLF , SHIP 1, and BCL 2. Consequently, the flavagline‐like compounds suppressed proliferation, induced apoptosis, and promoted erythroid differentiation of leukemic cells in culture. These compounds also suppressed erythroleukemogenesis in vivo in a Fli‐1‐driven mouse model. Mechanistically, the compounds blocked c‐Raf‐ MEK ‐ MAPK / ERK signaling, reduced phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), and inhibited Fli‐1 protein synthesis. Consistent with its high expression in myelomas, B‐cell lymphoma, and B chronic lymphocytic leukemia (B‐CLL), pharmacological inhibition of Fli‐1 by the flavagline‐like compounds or genetic knock‐down via sh RNA significantly hindered proliferation of corresponding cell lines and patients’ samples. These results uncover a critical role of Fli‐1 in growth and survival of various hematological malignancies and point to flavagline‐like agents as lead compounds for the development of anti‐Fli‐1 drugs to treat leukemias/lymphomas overexpressing Fli‐1.