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@ARTICLE{Wolf:131742,
      author       = {C. Wolf and A. Garding and K. Filarsky$^*$ and J. Bahlo and
                      S. Robrecht and N. Becker$^*$ and M. Zucknick and A. Rouhi
                      and A. Weigel and R. Claus and D. Weichenhan$^*$ and B.
                      Eichhorst and K. Fischer and M. Hallek and F. Kuchenbauer
                      and C. Plass$^*$ and H. Döhner and S. Stilgenbauer and P.
                      Lichter$^*$ and D. Mertens$^*$},
      title        = {{NFATC}1 activation by {DNA} hypomethylation in chronic
                      lymphocytic leukemia correlates with clinical staging and
                      can be inhibited by ibrutinib.},
      journal      = {International journal of cancer},
      volume       = {142},
      number       = {2},
      issn         = {0020-7136},
      address      = {Bognor Regis},
      publisher    = {Wiley-Liss},
      reportid     = {DKFZ-2018-00048},
      pages        = {322 - 333},
      year         = {2018},
      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.},
      keywords     = {Biomarkers, Tumor (NLM Chemicals) / NFATC Transcription
                      Factors (NLM Chemicals) / PCI 32765 (NLM Chemicals) /
                      Protein Kinase Inhibitors (NLM Chemicals) / Pyrazoles (NLM
                      Chemicals) / Pyrimidines (NLM Chemicals)},
      cin          = {B061 / B060 / C060 / C010},
      ddc          = {610},
      cid          = {I:(DE-He78)B061-20160331 / I:(DE-He78)B060-20160331 /
                      I:(DE-He78)C060-20160331 / I:(DE-He78)C010-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:28921505},
      doi          = {10.1002/ijc.31057},
      url          = {https://inrepo02.dkfz.de/record/131742},
}