Fig. 1

CLL main pathogenic pathways and target agents against BTK, PI3K and Bcl-2. BCR signaling is induced by the recognition of an antigen or by self-binding, Lyn promotes the phosphorylation of Iga and Igb that activates the spleen tyrosine kinase (Syk). Syk then triggers the formation of a multi-component ‘signalosome’, including Btk, Akt, PI3K and PLCγ2 among others. BCR co-receptor CD19 is important for PI3K activation, which recruits and activates PLCγ2, BTK and AKT. These leads to the activation of the c-Jun N-terminal kinase (JNK), MEK–extracellular signal-regulated kinase (ERK), mechanistic target of rapamycin (mTOR) and (NF-κB) signaling pathways. In addition, CLL cells activate these and other prosurvial, activatory pathways by their interaction with many soluble and surface factors. As an example: Wnt5a interact with the ROR1/ROR2 dimers promoting the activation of RhoA and Rac-1. CXCR4/CXCL12 engagement activates PI3K and downstream pathways, in addition other molecules. The TNF receptors CD40, BAFF-R, TACI and BCMA interact with their ligands CD40L or BAFF and APRIL, inducing the activation of the canonical and alternative NF-κB pathways depending on the TNF receptor-associated factor (TRAF). NOTCH1 signaling is initiated by the binding with one of the five ligands (e.g. jagged 1, Delta-like ligand 1 (DLL1)), followed by the release of the intracellular active portion (ICN1), enabling its migration into the nucleus. These pathways lead to the upregulation of anti-apoptotic molecules like Bcl-2, Bcl-XL and Mcl-1, sequestering the pro-apoptotic molecules Bax and Bak, and inhibiting the intrinsic apoptosis pathway. Inhibitors for PI3K, BTK and Bcl-2 are indicated in red