| 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
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| 2019-02-11 | |
| Source Publication | CELL DEATH & DISEASE
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| ISSN | 2041-4889 |
| Volume | 10Pages:11 |
| Abstract | 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. |
| Indexed By | SCI |
| Language | 英语 |
| Document Type | 期刊论文 |
| Identifier | http://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 Author | Hao, Xiaojiang; Ben-David, Yaacov |
| Affiliation | 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 |
| 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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| Liu-2019-Identificat（2055KB） | 期刊论文 | 出版稿 | 开放获取 | CC BY-NC-SA | View Download | |
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