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Originally published online as doi:10.2353/ajpath.2008.070294 on December 21, 2007

Published online before print December 21, 2007
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(American Journal of Pathology. 2008;172:215-224.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070294

Epigenetic Changes and Suppression of the Nuclear Factor of Activated T Cell 1 (NFATC1) Promoter in Human Lymphomas with Defects in Immunoreceptor Signaling

Askar Akimzhanov*, Laszlo Krenacs{dagger}, Timm Schlegel*, Stefan Klein-Hessling*, Enikö Bagdi{dagger}, Eva Stelkovics{dagger}, Eisaku Kondo{ddagger}, Sergei Chuvpilo*, Philipp Wilke*, Andris Avots*, Stefan Gattenlöhner*, Hans-Konrad Müller-Hermelink*, Alois Palmetshofer* and Edgar Serfling*

From the Institute of Pathology,*University of Wuerzburg, Wuerzburg, Germany; the Laboratory of Tumor Pathology and Molecular Diagnostics,{dagger}Institute of Biotechnology, Bay Zoltan Foundation for Applied Research, Szeged, Hungary; and the Department of Pathology,{ddagger}Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

The nuclear factor of activated T cell 1 (Nfatc1) locus is a common insertion site for murine tumorigenic retroviruses, suggesting a role of transcription factor NFATc1 in lymphomagenesis. Although NFATc1 is expressed in most human primary lymphocytes and mature human T- and B-cell neoplasms, we show by histochemical stainings that NFATc1 expression is suppressed in anaplastic large cell lymphomas and classical Hodgkin’s lymphomas (HLs). In HL cell lines, NFATc1 silencing correlated with a decrease in histone H3 acetylation, H3-K4 trimethylation, and Sp1 factor binding but with an increase in HP1 binding to the NFATC1 P1 promoter. Together with DNA hypermethylation of the NFATC1 P1 promoter, which we detected in all anaplastic large cell lymphoma and many HL lines, these observations reflect typical signs of transcriptional silencing. In several lymphoma lines, methylation of NFATC1 promoter DNA resulted in a "window of hypomethylation," which is flanked by Sp1-binding sites. Together with the under-representation of Sp1 at the NFATC1 P1 promoter in HL cells, this suggests that Sp1 factors can protect P1 DNA methylation in a directional manner. Blocking immunoreceptor signaling led to NFATC1 P1 promoter silencing and to a decrease in H3 acetylation and H3-K4 methylation but not DNA methylation. This shows that histone modifications precede the DNA methylation in NFATC1 promoter silencing.






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