Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis
Liu, Tangjingjun1,2,3; Xia, Lei1,2,3; Yao, Yao1,2,3; Yan, Chen4; Fan, Yanhua1,2,3; Gajendran, Babu1,2,3; Yang, Jue1,2,3; Li, You-Jun5; Chen, Juan5,6; Filmus, Jorge6; Spaner, David E.6; Zacksenhaus, Eldad7,8; Hao, Xiaojiang1,2,3,4; Ben-David, Yaacov1,2,3
2019-02-11
Source PublicationCELL DEATH & DISEASE
ISSN2041-4889
Volume10Pages:11
AbstractThe ETS transcription factor Fli-1 controls the expression of genes involved in hematopoiesis including cell proliferation, survival, and differentiation. Dysregulation of Fli-1 induces hematopoietic and solid tumors, rendering it an important target for therapeutic intervention. Through high content screens of a library of chemicals isolated from medicinal plants in China for inhibitors of a Fli-1 transcriptional reporter cells, we hereby report the identification of diterpenoid-like compounds that strongly inhibit Fli-1 transcriptional activity. These agents suppressed the growth of erythroleukemic cells by inducing apoptosis and differentiation. They also inhibited survival and proliferation of B-cell leukemic cell lines as well as primary B-cell lymphocytic leukemia (B-CLL) isolated from 7 patients. Moreover, these inhibitors blocked leukemogenesis in a mouse model of erythroleukemia, in which Fli-1 is the driver of tumor initiation. Computational docking analysis revealed that the diterpenoid-like compounds bind with high affinity to nucleotide residues in a pocket near the major groove within the DNA-binding sites of Fli-1. Functional inhibition of Fli-1 by these compounds triggered its further downregulation through miR-145, whose promoter is normally repressed by Fli-1. These results uncover the importance of Fli-1 in leukemogenesis, a Fli-1-miR145 autoregulatory loop and new anti-Fli-1 diterpenoid agents for the treatment of diverse hematological malignancies overexpressing this transcription factor.
Indexed BySCI
Language英语
Document Type期刊论文
Identifierhttp://ir.kib.ac.cn/handle/151853/65203
Collection植物化学与西部植物资源持续利用国家重点实验室
Corresponding AuthorHao, Xiaojiang; Ben-David, Yaacov
Affiliation1.Guizhou Med Univ, State Key Lab Funct & Applicat Med Plants, Guiyang 550025, Guizhou, Peoples R China
2.Key Lab Chem Nat Prod Guizhou Prov, Guiyang 550014, Guizhou, Peoples R China
3.Chinese Acad Sci, Guiyang 550014, Guizhou, Peoples R China
4.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming, Yunnan, Peoples R China
5.Jilin Univ, Dept Anat, Norman Bethune Coll Med, Changchun, Jilin, Peoples R China
6.Sunnybrook Res Inst, Biol Platform, Toronto, ON, Canada
7.Univ Toronto, Dept Med, Toronto, ON, Canada
8.Univ Hlth Network, Toronto Gen Res Inst, Div Adv Diagnost, Toronto, ON, Canada
Recommended Citation
GB/T 7714
Liu, Tangjingjun,Xia, Lei,Yao, Yao,et al. Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis[J]. CELL DEATH & DISEASE,2019,10:11.
APA Liu, Tangjingjun.,Xia, Lei.,Yao, Yao.,Yan, Chen.,Fan, Yanhua.,...&Ben-David, Yaacov.(2019).Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis.CELL DEATH & DISEASE,10,11.
MLA Liu, Tangjingjun,et al."Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis".CELL DEATH & DISEASE 10(2019):11.
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