Main therapeutic targets along the BCR signaling pathway in CLL cells

Main therapeutic targets along the BCR signaling pathway in CLL cells. Aggregation of the BCR by antigen induces the phosphorylation of the ITAMs within the cytoplasmic tails of the Ig-α/Ig-β heterodimer. Phosphorylation of the ITAMs is mediated by LYN or other members of the SRC family kinases. SYK is subsequently recruited to the phosphorylated ITAMs and activated by a multistep process that involves phosphorylation by SRC family kinases and trans-autophosphorylation. SYK further propagates the signal by phosphorylating and recruiting several signaling intermediates, such as BLNK, BCAP, VAV, SHC and PI3K. Recruitment of PI3K leads to the production of phosphatidylinositol-3,4,5-triphosphate (PIP3) and subsequent BTK and AKT activation. SYK and BTK then activate PLCγ2, which produces the second messengers inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). These second messengers induce the release of intracellular Ca2+ and activate PKC, which then activate the transcription factors NF-κB and NFAT. PKC also induces the expression of the phosphatase PTPN22, which dephosphorylates and inactivates LYN. This event prevents LYN-mediated recruitment and activation of the phosphatase SHIP, which is a key negative regulator of the PI3K/AKT pathway. In the absence of active SHIP, AKT continues to be activated by PIP3, resulting in amplification of the BCR survival signal. BCR signaling molecules that have been studied as potential therapeutic targets in CLL are depicted in grey.

Publication

Novel Agents and Emerging Strategies for Targeting the B-Cell Receptor Pathway in CLL. (2012) Dimitar G. Efremov, et al. Mediterr J Hematol Infect Dis. 2012;4(1):e2012067. Figure: F2. All organisms Mus musculus Homo sapiens Drosophila melanogaster Danio rerio

Disease mentions