IL-6 and/or IL-10 production by BTK^Cys481Ser-expressing cells confer a protective effect on BTK^WTMYD88-mutated WM and ABC DLBCL cells treated with ibrutinib. Nontransduced BTK^WT BCWM.1 (A) and TMD8 (B) cells were treated with a serial diluted ibrutinib in the presence or absence of cytokines (10 ng/mL CXCL-13, IL-6, IL-10, IL-12, TNF-α, TNF-β and 100 ng/mL MIP-1α, RANTES), and the relative fold change to no cytokine control in EC₅₀ for ibrutinib is shown. For Transwell coculture experiments, BTK^WT or BTK^Cys481Ser expressing BCWM.1 (C) or TMD8 (D) cells were pretreated with vehicle control or a serial diluted ibrutinib at indicated concentrations in the upper chambers of 0.4-μm filtered plates for 6 hours. Nontransduced counterparts were then added to lower chambers with or without blocking antibodies to IL-6 and IL-10 (10 μg/mL) for BCWM.1 WM cells, and to IL-10 alone (10 μg/mL) for TMD8 ABC DLBCL cells. Ibrutinib was then added to the lower chambers to keep the same concentrations and incubated for 72 hours. Viability was assessed by the CellTiter-Glo assay. The single (DMSO) line shows viability of nontransduced cells with drug vehicle control alone. The x-axis shows ibrutinib log concentration.