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

Molecular Cancer

Research

Xin Du¹  Suxia Geng¹  Jianyu Weng¹  Bing Xu²  Mei Zhong³  Yao Yao⁴  Lijian Yang⁵  Shaohua Chen⁵  Yangqiu Li⁵  Wei Li⁶  Donghai Wu⁶  Peng Li⁶  Yi Zheng⁶  Zhiwu Jiang⁶  Tianzhong Li⁶  Xinru Wei⁶  Xiaojun Huang⁷  Hudan Liu⁸  Yufeng Hu⁸  Hexiu Su⁸  Jue Jiang⁸  Minjie Zhang⁹  Pentao Liu^1,10 

[1] Department of Hematology, Guangdong Provincial People’s Hospital, 510500, Guangzhou, China;Department of Hematology, Nanfang Hospital, Southern Medical University, 510515, Guangzhou, China;Department of Obstetrics and Gynecology, Nan Fang Hospital of Southern Medical University, 510515, Guangzhou, China;Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, 510530, Guangzhou, Guangdong, China;Institute of Hematology, Medical College, Jinan University, 510632, Guangzhou, China;Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, 510632, Guangzhou, China;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, 510530, Guangzhou, Guangdong, China;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, 510530, Guangzhou, China;Peking University People’s Hospital, Peking University Institute of Hematology, No. 11 Xizhimen South St., 100044, Beijing, China;School of Pharmacy, Tongji Medical College, Huazhong Unviersity of Science and Technology, 13 Hangkong Road, 430030, Wuhan, China;Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, 1068 Xueyuan Avenue, Shenzhen University Town, 518055, Shenzhen, China;Wellcome Trust Sanger Institute, Hinxton, CB10 1HH, Cambridge, England, UK;

关键词: KLF4;    T-ALL;    T cell;    NOTCH1;    BCL11B;    Apoptosis;   

DOI  :  10.1186/s12943-014-0285-x

 received in 2014-09-23, accepted in 2014-12-29,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundKruppel-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.MethodsInducible 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.ResultsHere 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.ConclusionsThese results suggest that KLF4 as a major transcription factor that suppresses the expression of T-cell associated genes, thus inhibiting T-ALL progression.

【 授权许可】

CC BY   
© Li et al.; licensee BioMed Central. 2015