Role of BTK in signaling of the BCR, CXCR4, and TLRs in WM. Antigen binding by the BCR and/or ligand-independent tonic BCR signaling induces the formation of a signaling complex that is initiated by phosphorylation of immunoreceptor tyrosine-based activation motif residues on the cytoplasmic tails of CD79A (Igα) and CD79B (Igβ). In turn, this event recruits spleen tyrosine kinase (SYK), which is followed by the activation of BTK, PI3K, and phospholipase Cγ2 (PLCγ2). Further downstream responses include calcium (Ca²⁺) mobilization, activation of protein kinase C (PKC), and the ERK (MAPK) and nuclear factor-κB (NFκB) pathways. Most WM cells carry MYD88 and/or CXCR4 warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM)–like mutations, which result in enhanced signaling of CXCR4 and toll-like receptors (TLRs). Ibrutinib targets BTK and thereby can inhibit multiple pathways, including BCR signaling, CXCR4, and TLR signaling. BTK^Cys481Ser mutated WM cells emerge when WM patients develop ibrutinib resistance; such resistant cells have restored ERK signaling and secrete higher levels of IL-6 and IL-10, which can promote survival of BTK^WT cells in a paracrine fashion.