Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes

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• 作者：Wei Li (1) (2)
  Zhiwu Jiang (1) (2)
  Tianzhong Li (1) (2)
  Xinru Wei (1) (2)
  Yi Zheng (1) (2)
  Donghai Wu (1) (2)
  Lijian Yang (3) (4)
  Shaohua Chen (3) (4)
  Bing Xu (5)
  Mei Zhong (6)
  Jue Jiang (7)
  Yufeng Hu (7)
  Hexiu Su (7)
  Minjie Zhang (8)
  Xiaojun Huang (9)
  Suxia Geng (10)
  Jianyu Weng (10)
  Xin Du (10)
  Pentao Liu (11)
  Yangqiu Li (3) (4)
  Hudan Liu (7)
  Yao Yao (12)
  Peng Li (1) (2)
  
  1. 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
  2. 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
  3. Institute of Hematology ; Medical College ; Jinan University ; Guangzhou ; 510632 ; China
  4. Key Laboratory for Regenerative Medicine of Ministry of Education ; Jinan University ; Guangzhou ; 510632 ; China
  5. Department of Hematology ; Nanfang Hospital ; Southern Medical University ; 510515 ; Guangzhou ; China
  6. Department of Obstetrics and Gynecology ; Nan Fang Hospital of Southern Medical University ; Guangzhou ; 510515 ; China
  7. School of Pharmacy ; Tongji Medical College ; Huazhong Unviersity of Science and Technology ; 13 Hangkong Road ; Wuhan ; 430030 ; China
  8. Shenzhen Institutes of Advanced Technology ; Chinese Academy of Sciences ; 1068 Xueyuan Avenue ; Shenzhen University Town ; Shenzhen ; 518055 ; China
  9. Peking University People鈥檚 Hospital ; Peking University Institute of Hematology ; No. 11 Xizhimen South St. ; Beijing ; 100044 ; China
  10. Department of Hematology ; Guangdong Provincial People鈥檚 Hospital ; Guangzhou ; 510500 ; China
  11. Wellcome Trust Sanger Institute ; Hinxton ; Cambridge ; CB10 1HH ; England ; UK
  12. Drug Discovery Pipeline ; Guangzhou Institutes of Biomedicine and Health ; Chinese Academy of Sciences ; 190 Kaiyuan Avenue ; Science Park ; Guangzhou ; Guangdong ; 510530 ; China
  
• 关键词：KLF4 ; T ; ALL ; T cell ; NOTCH1 ; BCL11B ; Apoptosis
• 刊名：Molecular Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：14
• 期：1
• 全文大小：2,712 KB
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• 刊物主题：Cancer Research; Oncology;
• 出版者：BioMed Central
• ISSN：1476-4598

文摘

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.