Novel Therapeutic Target in Chronic Lymphocytic Leukemia Cells Identified

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BCR signaling–stimulation was linked to NFATC1 activation in CLL cells; inhibiting NFAT led to CLL cell apoptosis.
BCR signaling–stimulation was linked to NFATC1 activation in CLL cells; inhibiting NFAT led to CLL cell apoptosis.

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.

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

  1. 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]

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