Wolf C et al. -B cell receptor (BCR) signaling is key for survival of chronic lymphocytic leukemia (CLL). In the current study, novel candidate therapeutic options were evaluated. The activation of NFATC1 by DNA hypomethylation and BCR signaling was shown to have a major role in the pathomechanism of CLL.

Methods

• Genome-wide DNA methylation screening with custom arrays was performed to identify aberrant promoter DNA methylation in 2192 genes.

Results

• The transcription factor, NFATC1, was shown to be among the most common hypomethylated genes.
• NFATC1 was transcriptionally up-regulated in CLL.
• The findings suggested that NFATC1 has a central role in CLL development.
• DNA hypomethylation at the NFATC1 promoter was inversely correlated with RNA levels of NFATC1 and dysregulation was correlated with expression of target genes (BCL-2, CCND1, and CCR7).
• 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.
• NFAT inhibition resulted in increased apoptosis of primary CLL cells.