Critical molecular pathways in CLL therapy

Abstract

Chronic lymphocytic leukemia (CLL), the most frequent type of leukemia in western countries, is characterized by the progressive accumulation in blood, bone marrow and lymphoid tissues of monoclonal B lymphocytes with a characteristic immunophenotype. Despite advances in therapy and improved outcome, in most instances CLL is an incurable disorder. Signaling via the B-cell receptor (BCR), the upregulation of anti-apoptotic proteins, and the cross-talk between CLL cells and microenvironment constitute key factors in the pathogenesis of CLL. Currently, inhibitors of kinases like BTK or PI3K blocking BCR signaling, and molecules that mimic the BH3 domain to compete with BCL-2 are established tools in the treatment of CLL. As the complex biology of CLL is rapidly unfolding, the number of small molecules targeting CLL molecular pathways is increasing and it is likely that they will further improve the outcome of patients with this form of leukemia.

Keywords: BTK; Bcl-2 and pathway inhibitors; CLL; PI3K.

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