Figure 1.

Targeting of BCR and PI3K/AKT signaling as therapeutic strategy in CLL. BCR signaling has a major role in the development of CLL. After antigen ligation on BCR, three main protein tyrosine kinases, LYN, SYK and BTK, are activated. PLC2 and PI3K are important downstream effectors of BCR signaling. PI3K activates downstream kinases such as AKT, which in turn induces NFkB and mTOR routes. Activation of PLC2 leads to the release of intracellular Ca2+ and activation of PKC, both of which are crucial for the activation of mitogen-activated protein kinases (MAPKs), such as ERK, c-JUN NH2-terminal kinase (JNK) and p38 MAPK and transcription factors, including NFκB. PI3K/AKT pathway can be induced also by tyrosine kinase receptors such as IGFR1 and ROR1. TCL1 enhances AKT signal and can sustain activation of the BCR downstream factors SYK and LYN by indirect inhibition of the phosphatase PTPROt. Red symbols and letters indicate new therapeutic targets as discussed in the text