Figure 2.

Schematic representation of the BCR, CD40 and TLR signaling pathways. Upstream triggering of BCR, CD40, or TLR signaling lead to activation of similar downstream pathways, including the NF-kB, MEK/ERK, and PI3K/AKT/mTOR pathways. (A) The BCR is composed of an antigen-specific surface membrane immunoglobulin paired with the signal transduction component consisting of the CD79A/B heterodimer. Engagement of the BCR by antigen results in aggregation of BCR components that leads to the phosphorylation of ITAMs in the cytoplasmic tails of CD79A/B which triggers the recruitment and activation of the proximal tyrosine kinases LYN and SYK. Subsequently, BTK is activated which will activate PLCγ2 and BLNK, resulting in activation of downstream signaling pathways. (B) Upon binding of CD40L, the CD40 receptor on CLL cells trimerizes leading to the recruitment of TRAFs to the cytoplasmic domain of CD40. TRAFs may then cooperate in order to activate different signaling pathways downstream. (C) Upon TLR9 activation in the endosomal compartment of CLL cells, the TIR domain of TLR9 engages the TIR domain of the adaptor protein MyD88. MyD88 contains an IRAK1 domain which activates TRAF6, leading to the activation of downstream pathways.