Figure 1.

BCR signaling pathway and BTKis resistance in CLL. Upon antigen binding, the B cell receptor initiates the formation of a signaling complex through the phosphorylation of immunoreceptor-based activation motif (ITAM) residues on the cytoplasmic tails of CD79A(Igα) and CD79B(Igβ) proteins. This event activates SYK, which then triggers the activation of BTK, PLCγ2, and PI3K. The downstream signaling response includes PKC activation and Ca²⁺ mobilization and Akt activation, leading to the promotion of transcript factors NF-κB, ERK1/2, NFAT, and mTOR. This signaling cascade can be effectively inhibited by BTK inhibitors. However, BTK and PLCγ2 point mutations can result in BTKi resistance.