Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis

	Identification of diterpenoid compounds that interfere with Fli-1 DNA binding to suppress leukemogenesis
	Liu, Tangjingjun 1,2,3; Xia, Lei 1,2,3; Yao, Yao 1,2,3; Yan, Chen 4; Fan, Yanhua 1,2,3; Gajendran, Babu 1,2,3; Yang, Jue 1,2,3; Li, You-Jun 5; Chen, Juan 5,6; Filmus, Jorge 6; Spaner, David E.6; Zacksenhaus, Eldad 7,8; Hao, Xiaojiang1,2,3,4 ; Ben-David, Yaacov 1,2,3
	2019-02-11
发表期刊	CELL DEATH & DISEASE
ISSN	2041-4889
卷号	10 页码:11
摘要	The 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.
收录类别	SCI
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/65203
专题	植物化学与西部植物资源持续利用国家重点实验室
通讯作者	Hao, Xiaojiang; Ben-David, Yaacov
作者单位	1.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
推荐引用方式 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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