title: Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes.
abstract: 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.
authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. li_wei2011@gibh.ac.cn.|Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. li_wei2011@gibh.ac.cn.
authors: Wei
authors: W
authors: Li
authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. jiang_zhiwu@gibh.ac.cn.|Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. jiang_zhiwu@gibh.ac.cn.
authors: Zhiwu
authors: Z
authors: Jiang
authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. li_tianzhong@gibh.ac.cn.|Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. li_tianzhong@gibh.ac.cn.
authors: Tianzhong
authors: T
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authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. wei_xinru@gibh.ac.cn.|Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. wei_xinru@gibh.ac.cn.
authors: Xinru
authors: X
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authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. zheng_yi@gibh.ac.cn.|Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. zheng_yi@gibh.ac.cn.
authors: Yi
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authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. wu_donghai@gibh.ac.cn.|Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. wu_donghai@gibh.ac.cn.
authors: Donghai
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authors: Institute of Hematology, Medical College, Jinan University, Guangzhou, 510632, China. jnyanglijian@163.com.|Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, China. jnyanglijian@163.com.
authors: Lijian
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authors: Yang
authors: Institute of Hematology, Medical College, Jinan University, Guangzhou, 510632, China. jnshaohuachen@163.com.|Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, China. jnshaohuachen@163.com.
authors: Shaohua
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authors: Chen
authors: Department of Hematology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China. xubingzhangjian@126.com.
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authors: Department of Obstetrics and Gynecology, Nan Fang Hospital of Southern Medical University, Guangzhou, 510515, China. zhongmei@fimmu.com.
authors: Mei
authors: M
authors: Zhong
authors: School of Pharmacy, Tongji Medical College, Huazhong Unviersity of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China. jiang1@hotmail.com.
authors: Jue
authors: J
authors: Jiang
authors: School of Pharmacy, Tongji Medical College, Huazhong Unviersity of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China. yufenghu@hust.edu.cn.
authors: Yufeng
authors: Y
authors: Hu
authors: School of Pharmacy, Tongji Medical College, Huazhong Unviersity of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China. suhexiu@hust.edu.cn.
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authors: H
authors: Su
authors: Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Shenzhen University Town, Shenzhen, 518055, China. minjie.zhang@gmail.com.
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authors: M
authors: Zhang
authors: Peking University People's Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South St., Beijing, 100044, China. xjhrm@medmail.com.cn.
authors: Xiaojun
authors: X
authors: Huang
authors: Department of Hematology, Guangdong Provincial People's Hospital, Guangzhou, 510500, China. gsx76@126.com.
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authors: S
authors: Geng
authors: Department of Hematology, Guangdong Provincial People's Hospital, Guangzhou, 510500, China. wsswjy@sina.com.
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authors: J
authors: Weng
authors: Department of Hematology, Guangdong Provincial People's Hospital, Guangzhou, 510500, China. miyadu@hotmail.com.
authors: Xin
authors: X
authors: Du
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, England, UK. pl2@sanger.ac.uk.
authors: Pentao
authors: P
authors: Liu
authors: Institute of Hematology, Medical College, Jinan University, Guangzhou, 510632, China. yangqiuli@hotmail.com.|Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, China. yangqiuli@hotmail.com.
authors: Yangqiu
authors: Y
authors: Li
authors: School of Pharmacy, Tongji Medical College, Huazhong Unviersity of Science and Technology, 13 Hangkong Road, Wuhan, 430030, China. hudanliu@hust.edu.cn.
authors: Hudan
authors: H
authors: Liu
authors: Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. yao_yao@gibh.ac.cn.
authors: Yao
authors: Y
authors: Yao
authors: Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong, 510530, China. li_peng@gibh.ac.cn.|Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, 510530, China. li_peng@gibh.ac.cn.
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authors: Li
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D015870:Gene Expression; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D055106:Genome-Wide Association Study; D064593:Heterografts; D006801:Humans; D019169:Jurkat Cells; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D059748:Proteolysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C479740:BCL11B protein, human; C494811:BCL2L1 protein, human; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D019253:Proto-Oncogene Proteins c-bcl-2; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein
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