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: Wei Li, Zhiwu Jiang, Tianzhong Li, Xinru Wei, Yi Zheng, Donghai Wu, Lijian Yang, Shaohua Chen, Bing Xu, Mei Zhong, Jue Jiang, Yufeng Hu, Hexiu Su, Minjie Zhang, Xiaojun Huang, Suxia Geng, Jianyu Weng, Xin Du, Pentao Liu, Yangqiu Li, Hudan Liu, Yao Yao, Peng Li
• Journal: Molecular cancer (Mol Cancer) Vol. 14 Pg. 26 (Feb 03 2015) ISSN: 1476-4598 [Electronic] England
• PMID: 25644173 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCL11B protein, human
• BCL2L1 protein, human
• KLF4 protein, human
• Klf4 protein, mouse
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors
• Proto-Oncogene Proteins c-bcl-2
• Repressor Proteins
• Tumor Suppressor Proteins
• bcl-X Protein

Topics

• Animals
• Apoptosis (genetics)
• Cluster Analysis
• Disease Models, Animal
• Disease Progression
• Down-Regulation
• Gene Expression
• Gene Expression Profiling
• Gene Expression Regulation, Leukemic
• Genome-Wide Association Study
• Heterografts
• Humans
• Jurkat Cells
• Kruppel-Like Factor 4
• Kruppel-Like Transcription Factors (genetics, metabolism)
• Mice
• Models, Biological
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism)
• Proteolysis
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Repressor Proteins (metabolism)
• Signal Transduction
• Sumoylation
• Tumor Suppressor Proteins (metabolism)
• bcl-X Protein (metabolism)