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

TitleGenome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes
Authors
KeywordsNOTCH1
T-ALL
Apoptosis
BCL11B
KLF4
T cell
Issue Date2015
Citation
Molecular Cancer, 2015, v. 14, n. 1 How to Cite?
Abstractà © 2015 Li et al. 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.
Persistent Identifierhttp://hdl.handle.net/10722/249119
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLi, Wei-
dc.contributor.authorJiang, Zhiwu-
dc.contributor.authorLi, Tianzhong-
dc.contributor.authorWei, Xinru-
dc.contributor.authorZheng, Yi-
dc.contributor.authorWu, Donghai-
dc.contributor.authorYang, Lijian-
dc.contributor.authorChen, Shaohua-
dc.contributor.authorXu, Bing-
dc.contributor.authorZhong, Mei-
dc.contributor.authorJiang, Jue-
dc.contributor.authorHu, Yufeng-
dc.contributor.authorSu, Hexiu-
dc.contributor.authorZhang, Minjie-
dc.contributor.authorHuang, Xiaojun-
dc.contributor.authorGeng, Suxia-
dc.contributor.authorWeng, Jianyu-
dc.contributor.authorDu, Xin-
dc.contributor.authorLiu, Pentao-
dc.contributor.authorLi, Yangqiu-
dc.contributor.authorLiu, Hudan-
dc.contributor.authorYao, Yao-
dc.contributor.authorLi, Peng-
dc.date.accessioned2017-10-27T05:59:09Z-
dc.date.available2017-10-27T05:59:09Z-
dc.date.issued2015-
dc.identifier.citationMolecular Cancer, 2015, v. 14, n. 1-
dc.identifier.urihttp://hdl.handle.net/10722/249119-
dc.description.abstractà © 2015 Li et al. 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.-
dc.languageeng-
dc.relation.ispartofMolecular Cancer-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectNOTCH1-
dc.subjectT-ALL-
dc.subjectApoptosis-
dc.subjectBCL11B-
dc.subjectKLF4-
dc.subjectT cell-
dc.titleGenome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through directly inhibiting T-cell associated genes-
dc.typeArticle-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12943-014-0285-x-
dc.identifier.pmid25644173-
dc.identifier.scopuseid_2-s2.0-84961512480-
dc.identifier.volume14-
dc.identifier.issue1-
dc.identifier.spagenull-
dc.identifier.epagenull-
dc.identifier.eissn1476-4598-
dc.identifier.isiWOS:000350502800001-

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