Journal Article

DKFZ-2018-00048

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib.

Wolf, C. (First author) ; Garding, A. ; Filarsky, K.DKFZ* ; Bahlo, J. ; Robrecht, S. ; Becker, N.DKFZ* ; Zucknick, M. ; Rouhi, A. ; Weigel, A. ; Claus, R. ; Weichenhan, D.DKFZ* ; Eichhorst, B. ; Fischer, K. ; Hallek, M. ; Kuchenbauer, F. ; Plass, C.DKFZ* ; Döhner, H. ; Stilgenbauer, S. ; Lichter, P.DKFZ* ; Mertens, D. (Last author)DKFZ*

2018
Wiley-Liss Bognor Regis

This record in other databases:  

Please use a persistent id in citations: doi:10.1002/ijc.31057

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.

Keyword(s): Biomarkers, Tumor ; NFATC Transcription Factors ; PCI 32765 ; Protein Kinase Inhibitors ; Pyrazoles ; Pyrimidines

---

Contributing Institute(s):

1. B061 Mechanismen der Leukämogenese (B061)
2. B060 Molekulare Genetik (B060)
3. C060 Biostatistik (C060)
4. Epigenomik und Krebsrisikofaktoren (C010)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2018

---

Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; IF >= 5 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

---