Wolf, Christine, Garding, Angela, Filarsky, Katharina, Bahlo, Jasmin, Robrecht, Sandra, Becker, Natalia, Zucknick, Manuela ORCID: 0000-0003-1317-7422, Rouhi, Arefeh, Weigel, Anja, Claus, Rainer ORCID: 0000-0003-2617-8766, Weichenhan, Dieter, Eichhorst, Barbara, Fischer, Kirsten, Hallek, Michael, Kuchenbauer, Florian, Plass, Christoph, Doehner, Hartmut, Stilgenbauer, Stephan, Lichter, Peter and Mertens, Daniel ORCID: 0000-0003-0227-7188 (2018). NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib. Int. J. Cancer, 142 (2). S. 322 - 334. HOBOKEN: WILEY. ISSN 1097-0215

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wolf, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Garding, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Filarsky, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bahlo, JasminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robrecht, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, NataliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zucknick, ManuelaUNSPECIFIEDorcid.org/0000-0003-1317-7422UNSPECIFIED
Rouhi, ArefehUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weigel, AnjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Claus, RainerUNSPECIFIEDorcid.org/0000-0003-2617-8766UNSPECIFIED
Weichenhan, DieterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichhorst, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuchenbauer, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Plass, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doehner, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lichter, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens, DanielUNSPECIFIEDorcid.org/0000-0003-0227-7188UNSPECIFIED
URN: urn:nbn:de:hbz:38-198882
DOI: 10.1002/ijc.31057
Journal or Publication Title: Int. J. Cancer
Volume: 142
Number: 2
Page Range: S. 322 - 334
Date: 2018
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1097-0215
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
KAPPA-B ACTIVATION; DOWN-REGULATION; PHOSPHATIDYLINOSITOL 3-KINASE; SIGNALING PATHWAY; CYCLOSPORINE-A; CYCLIN D1; IN-VITRO; METHYLATION; EXPRESSION; GENEMultiple languages
OncologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19888

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