NFATC1 activation, which occurs downstream of B cell receptor signaling, prevents apoptosis of chronic lymphocytic leukemia (CLL) cells and may represent a therapeutic target in the relapsed/refractory disease setting, according to a paper published in the International Journal of Cancer.1
Ibrutinib, a B cell receptor signaling inhibitor, is clinically efficacious in CLL, though patients often develop resistance or are refractory to this treatment. To determine viable treatment targets in the relapsed/refractory CLL setting, researchers screened for abnormal DNA methylation in 2192 genes, comparing samples from 13 patients with CLL with those of 6 healthy controls.
Among CLL samples, NFATC1 was the fourth most-hypomethylated gene evaluated; NFATC1 hypomethylation levels also correlated with patient disease stage.
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BCR signaling–stimulation was linked to NFATC1 activation in CLL cells; inhibiting NFAT led to CLL cell apoptosis.
The authors concluded that “[these] findings of the central role of NFATC1 in the pathomechanism of CLL are another step towards elucidating the underlying functional circuitry,” and that “[B cell receptor]-NFAT signaling cascade components could serve as promising targets.”
Reference
- Wolf C, Garding A, Filarsky K, et al. NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib. Int J Cancer. 2017 Sep 18. doi: 10.1002/ijc.31057 [Epub ahead of print]
