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Genome-wide analyses identify KLF4 as an important negative regulator in T-cell acute lymphoblastic leukemia through
Wei Li1,2, Zhiwu Jiang3,4, Tianzhong Li5,6
1Key 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.
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.
Insights
Kruppel-like factor 4 (KLF4) suppresses T-cell acute lymphoblastic leukemia (T-ALL) progression by inhibiting key T-cell genes. KLF4 induces apoptosis and reduces T-ALL cell invasion, offering a potential therapeutic target.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Kruppel-like factor 4 (KLF4) has context-dependent roles in tumorigenesis.
- The function and mechanisms of KLF4 in hematological malignancies, particularly T-cell acute lymphoblastic leukemia (T-ALL), remain unclear.
Purpose of the Study:
- To investigate the role of KLF4 in T-ALL.
- To elucidate the molecular mechanisms by which KLF4 affects T-ALL progression.
Main Methods:
- Utilized KLF4-overexpressing Jurkat cells, mouse xenograft models, and primary T-ALL patient samples.
- Performed genome-wide RNA sequencing (RNA-seq) to identify KLF4-regulated genes.
- Employed chromatin immunoprecipitation (ChIP) PCR to determine KLF4 direct binding sites.
Main Results:
- KLF4 overexpression induced apoptosis in T-ALL cells via the BCL2/BCLXL pathway and prolonged survival in vivo.
- KLF4 suppressed T-cell associated genes (NOTCH1, BCL11B, GATA3, TCF7) by direct promoter binding and induced BCL11B degradation.
- KLF4 reduced T-ALL cell invasion capacity despite compromised apoptosis in xenografts.
Conclusions:
- KLF4 acts as a transcription factor that suppresses T-cell associated gene expression.
- KLF4 inhibits T-ALL progression, suggesting its potential as a therapeutic target.
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