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学科主题: 临床医学
题名:
Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes
作者: Li, Wei1,2; Jiang, Zhiwu1,2; Li, Tianzhong1,2; Wei, Xinru1,2; Zheng, Yi1,2; Wu, Donghai1,2; Yang, Lijian3,4; Chen, Shaohua3,4; Xu, Bing5; Zhong, Mei6; Jiang, Jue7; Hu, Yufeng7; Su, Hexiu7; Zhang, Minjie8; Huang, Xiaojun9; Geng, Suxia10; Weng, Jianyu10; Du, Xin10; Liu, Pentao11; Li, Yangqiu3,4; Liu, Hudan; Yao, Yao2,12; Li, Peng1,2
关键词: KLF4 ; T-ALL ; T cell ; NOTCH1 ; BCL11B ; Apoptosis
刊名: MOLECULAR CANCER
发表日期: 2015-02-03
DOI: 10.1186/s12943-014-0285-x
卷: 14
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Biochemistry & Molecular Biology ; Oncology
研究领域[WOS]: Biochemistry & Molecular Biology ; Oncology
关键词[WOS]: EMBRYONIC STEM-CELLS ; RNA-SEQ ; DOWN-REGULATION ; B-CELL ; TRANSCRIPTIONAL NETWORK ; FAT1 CADHERIN ; BCL11B ; EXPRESSION ; DIFFERENTIATION ; MIGRATION
英文摘要:

Background: Kruppel-like factor 4 (KLF4) induces tumorigenesis or suppresses tumor growth in a tissue-dependent manner. However, the roles of KLF4 in hematological malignancies and the mechanisms of action are not fully understood.

Methods: Inducible KLF4-overexpression Jurkat cell line combined with mouse models bearing cell-derived xenografts and primary T-cell acute lymphoblastic leukemia (T-ALL) cells from four patients were used to assess the functional role of KLF4 in T-ALL cells in vitro and in vivo. A genome-wide RNA-seq analysis was conducted to identify genes regulated by KLF4 in T-ALL cells. Chromatin immunoprecipitation (ChIP) PCR was used to determine direct binding sites of KLF4 in T-ALL cells.

Results: Here we reveal that KLF4 induced apoptosis through the BCL2/BCLXL pathway in human T-ALL cell lines and primary T-ALL specimens. In consistence, mice engrafted with KLF4-overexpressing T-ALL cells exhibited prolonged survival. Interestingly, the KLF4-induced apoptosis in T-ALL cells was compromised in xenografts but the invasion capacity of KLF4-expressing T-ALL cells to hosts was dramatically dampened. We found that KLF4 overexpression inhibited T cell-associated genes including NOTCH1, BCL11B, GATA3, and TCF7. Further mechanistic studies revealed that KLF4 directly bound to the promoters of NOTCH1, BCL2, and CXCR4 and suppressed their expression. Additionally, KLF4 induced SUMOylation and degradation of BCL11B.

Conclusions: These results suggest that KLF4 as a major transcription factor that suppresses the expression of T-cell associated genes, thus inhibiting T-ALL progression.

语种: 英语
所属项目编号: XDA01020310 ; 81272329 ; 81200255 ; 81327801 ; 81272211 ; 81200381 ; 2011CB504004 ; 2010CB945500 ; yg2010080 ; yg2011082 ; yg2012049
项目资助者: Strategic Priority Research Program of the Chinese Academy of Sciences ; National Natural Science Foundation of China ; National Basic Research Program of China (973 Program) ; Equipment Function Development &amp ; Technology Innovation Project of Chinese Academy of Sciences
WOS记录号: WOS:000350502800001
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62368
Appears in Collections:北京大学第二临床医学院_血液科_期刊论文

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作者单位: 1.Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England
2.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Key Lab Regenerat Biol, Guangzhou 510530, Guangdong, Peoples R China
3.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, South China Inst Stem Cell Biol & Regenerat Med, Guangdong Prov Key Lab Stem Cell & Regenerat Med, Guangzhou 510530, Guangdong, Peoples R China
4.Jinan Univ, Coll Med, Inst Hematol, Guangzhou 510632, Guangdong, Peoples R China
5.Jinan Univ, Lab Regenerat Med, Minist Educ, Guangzhou 510632, Guangdong, Peoples R China
6.Southern Med Univ, Nanfang Hosp, Dept Hematol, Guangzhou 510515, Guangdong, Peoples R China
7.Southern Med Univ, Nan Fang Hosp, Dept Obstet & Gynecol, Guangzhou 510515, Guangdong, Peoples R China
8.Huazhong Univ Sci & Technol, Tongji Med Coll, Sch Pharm, Wuhan 430030, Peoples R China
9.Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen 518055, Peoples R China
10.Peking Univ, Peoples Hosp, Inst Hematol, Beijing 100044, Peoples R China
11.Guangdong Prov Peoples Hosp, Dept Hematol, Guangzhou 510500, Guangdong, Peoples R China
12.Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Drug Discovery Pipeline, Guangzhou 510530, Guangdong, Peoples R China

Recommended Citation:
Li, Wei,Jiang, Zhiwu,Li, Tianzhong,et al. Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes[J]. MOLECULAR CANCER,2015,14.
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