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000131742 1001_ $$aWolf, Christine$$b0$$eFirst author
000131742 245__ $$aNFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib.
000131742 260__ $$aBognor Regis$$bWiley-Liss$$c2018
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000131742 520__ $$aB 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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000131742 650_7 $$2NLM Chemicals$$aBiomarkers, Tumor
000131742 650_7 $$2NLM Chemicals$$aNFATC Transcription Factors
000131742 650_7 $$2NLM Chemicals$$aPCI 32765
000131742 650_7 $$2NLM Chemicals$$aProtein Kinase Inhibitors
000131742 650_7 $$2NLM Chemicals$$aPyrazoles
000131742 650_7 $$2NLM Chemicals$$aPyrimidines
000131742 7001_ $$aGarding, Angela$$b1
000131742 7001_ $$0P:(DE-He78)cadc08f6f4a17b1b7b8c4038ae6aa44a$$aFilarsky, Katharina$$b2
000131742 7001_ $$aBahlo, Jasmin$$b3
000131742 7001_ $$aRobrecht, Sandra$$b4
000131742 7001_ $$0P:(DE-He78)ecb33fb615e08035fdcefcaebfdff8f0$$aBecker, Natalia$$b5
000131742 7001_ $$aZucknick, Manuela$$b6
000131742 7001_ $$aRouhi, Arefeh$$b7
000131742 7001_ $$aWeigel, Anja$$b8
000131742 7001_ $$aClaus, Rainer$$b9
000131742 7001_ $$0P:(DE-He78)ff4024f7bc236e7897d9c18ee19c451f$$aWeichenhan, Dieter$$b10
000131742 7001_ $$aEichhorst, Barbara$$b11
000131742 7001_ $$aFischer, Kirsten$$b12
000131742 7001_ $$aHallek, Michael$$b13
000131742 7001_ $$aKuchenbauer, Florian$$b14
000131742 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b15
000131742 7001_ $$aDöhner, Hartmut$$b16
000131742 7001_ $$aStilgenbauer, Stephan$$b17
000131742 7001_ $$0P:(DE-He78)e13b4363c5fe858044ef8a39c02c870c$$aLichter, Peter$$b18
000131742 7001_ $$0P:(DE-He78)833c06a995d272b78f3a20df3eba6e9e$$aMertens, Daniel$$b19$$eLast author$$udkfz
000131742 773__ $$0PERI:(DE-600)1474822-8$$a10.1002/ijc.31057$$gVol. 142, no. 2, p. 322 - 333$$n2$$p322 - 333$$tInternational journal of cancer$$v142$$x0020-7136$$y2018
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