CLL cells in lymph node and bone marrow microenvironments demonstrate higher levels of BCR and NF-κB signaling as well as increased cell activation and proliferation.

Evaluating long-term effects of ibrutinib in tissue compartment.

BCR signaling significantly inhibited in CLL cells.

Also found inhibition of the NF-κB gene signature.

Reduction in both signatures, but substantial variation in extent.

Variability did correlate with clinical and prognostic factors.

Degree of inhibition of NF-κB signaling strongly correlated with degree of inhibition of BCR signaling.

CLL cells showed significant reduction in both PLCγ2 and ERK phosphorylation.

Significant reduction in cell surface expression of activation markers CD69 and CD86, respectively.

Ibrutinib effectively inhibits BCR, NF-κB, and ERK signaling.

Very quick response in lymph node and sustained on treatment as shown in bone marrow.

BTK is central hub mediating nourishing and protective effects of tumor microenvironment.