Kruppel-like factor 4 (KLF4) inactivation in chronic lymphocytic leukemia correlates with promoter DNA-methylation and can be reversed by inhibition of NOTCH signaling

Filarsky, Katharina; Garding, Angela; Becker, Natália; Wolf, Christine; Zucknick, Manuela; Claus, Rainer; Weichenhan, Dieter; Plass, Christoph; Döhner, Hartmut; Stilgenbauer, Stephan; Lichter, Peter; Mertens, Daniel

doi:10.3324/haematol.2015.138172

Cited by 26 publications

(35 citation statements)

References 15 publications

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“…However, here we found small but significant differences in the expression of CCND1 between bulk normal and CLL B cells, suggesting that there might be either small expression differences in the whole population or larger differences in small subpopulations. In contrast, there is no significant correlation of expression levels of BAK and BAX with NFATC1 ( r = −0.182 and −0.235; p = 0.5 and 0.3), although these genes are also differentially expressed in CLL cells …”

Section: Resultsmentioning

confidence: 93%

“…To identify genes in CLL cells that are most affected by aberrant DNA methylation and are candidates for disease development and progression, we performed a genome‐wide screen for DNA methylation of gene promoters in primary CD19+ sorted CLL cells and normal B cells . DNA isolated from 13 CLL patients and 6 healthy donors was applied to methyl‐CpG‐immunoprecipitation (MCIp), and highly methylated DNA was hybridized to custom promoter tiling‐arrays covering −3.8 to +1.8 kb from the transcription start site (TSS) of human RefSeq genes.…”

Section: Resultsmentioning

confidence: 99%

“…Genome‐wide promoter DNA methylation was analyzed using MCIp‐array as described previously . Briefly, MCIp samples were hybridized to custom promoter tiling‐arrays covering −3.8 to +1.8 kb from the transcription start site (TSS) of human RefSeq genes (Agilent, Santa Clara, CA).…”

Section: Methodsmentioning

confidence: 99%

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NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib

Wolf

Garding

Filarsky

et al. 2017

Intl Journal of Cancer

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B cell receptor (BCR) signaling is a key for survival of chronic lymphocytic leukemia (CLL) cells, and BCR signaling inhibitors are clinically active. However, relapse and resistance to treatment require novel treatment options. To detect novel candidate therapeutic targets, we performed a genome-wide DNA methylation screen with custom arrays and identified aberrant promoter DNA methylation in 2,192 genes. The transcription factor NFATC1 that is a downstream effector of BCR signaling was among the top hypomethylated genes and was concomitantly transcriptionally upregulated in CLL. Intriguingly, NFATC1 promoter DNA hypomethylation levels were significantly variant in clinical trial cohorts from different disease progression stages and furthermore correlated with Binet disease staging and thymidine kinase levels, strongly suggesting a central role of NFATC1 in CLL development. Functionally, DNA hypomethylation at NFATC1 promoter inversely correlated with RNA levels of NFATC1 and dysregulation correlated with expression of target genes BCL-2, CCND1 and CCR7. The inhibition of the NFAT regulator calcineurin with tacrolimus and cyclosporin A and the BCR signaling inhibitor ibrutinib significantly reduced NFAT activity in leukemic cell lines, and NFAT inhibition resulted in increased apoptosis of primary CLL cells. In summary, our results indicate that the aberrant activation of NFATC1 by DNA hypomethylation and BCR signaling plays a major role in the pathomechanism of CLL.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

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NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib

Wolf

Garding

Filarsky

et al. 2017

Intl Journal of Cancer

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“…Supporting a correlation between KLF4 promoter methylation and gene expression, the treatment of T-ALL cell lines with 5-azacytidine (5-AZA) restored the expression of KLF4 and consequently inhibited cell proliferation and induced apoptosis. KLF4 inactivation by DNA methylation has also been described in numerous cancer types such as esophageal squamous cell carcinoma, gastric, oral carcinoma, cervical, urothelial, renal carcinoma, lymphoma, medulloblastoma, colorectal carcinoma, and, more recently, chronic lymphocytic leukemia (19, 33–42). …”

Section: Emerging Role Of Klf4 In Hematological Malignanciesmentioning

confidence: 96%

Novel tumor-suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemia

Chen

Lacorazza

2017

Experimental Hematology

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Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy in pediatric patients. Despite advances in the treatment of this disease, many children with T-cell ALL (T-ALL) die from disease relapse due to low responses to standard chemotherapy and the lack of a targeted therapy that selectively eradicates the chemoresistant leukemia-initiating cells (LICs) responsible for disease recurrence. We recently reported that the reprogramming factor KLF4 has tumor-suppressive function in children with T-ALL. KLF4 silencing by promoter DNA methylation in patients with T-ALL leads to aberrant activation of MAP2K7 kinase and the downstream JNK pathway that controls the expansion of leukemia cells via c-JUN and ATF2. This pathway can be inhibited with small molecules and therefore has the potential to eliminate LICs and eradicate disease in combination with standard therapy for patients with refractory and relapsed disease. The present review summarizes the role of the KLF4-MAP2K7 pathway in T-ALL pathogenesis and the function of JNK and MAP2K7 in carcinogenesis and therapy.

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“…Interestingly, another key focus of the current study, the KLF4 gene, plays critical roles in cell growth, proliferation and differentiation, and has been further reported to potentially act as a tumour suppressor in prostate cancer owing to its decreased expression, which could be used to predict the prognosis of this cancer 24. This specific process of abnormal DNA methylation is associated with gene expression,27 and another study also noted that the expression of KLF4 could be depleted by promoter methylation in classical Hodgkin lymphoma cells 28. Additionally, our findings demonstrated that LINC00673 could augment the methylation of the KLF4 gene promoter to consequently down-regulate the expression of KLF4.…”

mentioning

confidence: 89%

Long non‐coding RNA LINC00673 silencing inhibits proliferation and drug resistance of prostate cancer cells via decreasing KLF4 promoter methylation

Jiang

Zhang

Chen

et al. 2019

J Cellular Molecular Medi

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| INTRODUC TI ONAs a non-skin tumour accompanied by variable natural history, prostate cancer is a highly prevalent malignancy and represents one of the leading causes of cancer-related deaths in the male populace. 1,2 Risk factors responsible for prostate cancer comprise smoking, alcohol consumption and levels of male androgens. 3 Paclitaxel is widely regarded as an essential important drug for prostate cancer treatment; however, paclitaxel resistance ensues in many prostate cancer patients, which highlights the significance of developing strategies AbstractProstate cancer is one of the major causes of cancer-related mortality in men across the world. Recently, long non-coding RNAs (lncRNAs) and Kruppel-like factor 4 (KLF4) have been reported to participate in the biology of multiple cancers including prostate cancer. Here, this study aimed to explore the possible role of LINC00673 in prostate cancer via KLF4 gene promoter methylation. Microarray-based gene expression profiling of prostate cancer was employed to identify differentially expressed lncRNAs and genes, after which the expression of LINC00673 and KLF4 in prostate cancer tissues was determined using RT-qPCR. Next, the relationship between LINC00673 and KLF4 was evaluated using in silico analysis. Further, the effect of LINC00673 and KLF4 on cell proliferation and drug resistance of transfected cells was examined with gain-and loss-of-function experimentation. It was found that LINC00673 was highly expressed, while KLF4 was poorly expressed in prostate cancer tissues. Additionally, LINC00673 could bind to KLF4 gene promoter region and recruit methyltransferase to the KLF4 gene promoter region. Moreover, LINC00673silencing was demonstrated to reduce methylation of the KLF4 gene promoter to elevate the expression of KLF4, thus suppressing the proliferation and drug resistance of prostate cancer cells. In summary, LINC00673 silencing could drive demethylation of the KLF4 gene promoter and thus inhibit the proliferation and drug resistance of prostate cancer cells, suggesting that silencing of LINC00673 and elevation of KLF4 could serve as tumour suppressors in prostate cancer.

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Kruppel-like factor 4 (KLF4) inactivation in chronic lymphocytic leukemia correlates with promoter DNA-methylation and can be reversed by inhibition of NOTCH signaling

Cited by 26 publications

References 15 publications

NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib

NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib

Novel tumor-suppressor function of KLF4 in pediatric T-cell acute lymphoblastic leukemia

Long non‐coding RNA LINC00673 silencing inhibits proliferation and drug resistance of prostate cancer cells via decreasing KLF4 promoter methylation

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