B cell receptor signaling in chronic lymphocytic leukemia

Abstract

B cell receptor (BCR) signaling plays an important pathogenic role in chronic lymphocytic leukemia (CLL) and B cell lymphomas, based on structural restrictions of the BCR, and BCR-dependent survival and growth of the malignant B cells. In CLL and lymphoma subtypes, ligand-independent ('tonic') and ligand-dependent BCR signaling have been characterized, which can involve mutations of BCR pathway components or be triggered by (auto)antigens present in the tissue microenvironment. In CLL, based on high response rates and durable remissions in early-stage clinical trials, there is rapid clinical development of inhibitors targeting BCR-associated kinases [Bruton's tyrosine kinase (BTK), phosphoinositide 3-kinase (PI3K)δ], which will change treatment paradigms in CLL and other B cell malignancies. Here, we discuss the evolution of this field, from BCR-related prognostic markers, to mechanisms of BCR activation, and targeting of BCR-associated kinases, the emerging Achilles' heel in CLL pathogenesis.

Keywords: B cell receptor; Bruton's tyrosine kinase; chronic lymphocytic leukemia; microenvironment; phosphoinositide 3-kinase δ; spleen tyrosine kinase.

Figure 1. BCR components and upstream signaling

The BCR consists of the antigen-binding heavy chains IgH (VH and CH1-4) and light chains IgL (VL and CL) that are noncovalently coupled to the Ig-α (CD79A) and Ig-β (CD79B) signaling subunits. Antigen encounter and BCR clustering promotes tyrosine phosphorylation of the immunoreceptor tyrosine-based activation motif (ITAMs) by Src-family kinases LYN, FYN, and BLK. Phosphorylated ITAMs then recruit SYK through interactions with its SH2 domains. SYK activation triggers activation of a signaling cascade that engages BTK, PI3Ks (including PI3Kδ), NF-κB, PI3K, NF-AT, MAP kinase, and RAS signaling pathways, leading to cell survival and proliferation. Upstream BCR signaling kinases can be targeted by the small molecule SYK inhibitor fostamatinib [90], the BTK inhibitor ibrutinib[91], and the PI3Kδ inhibitor idelalisib[117].

Figure 2. Mechanism of BCR activation in CLL

(A) BCR signaling can be activated in an exo-antigen-independent fashion, for example by interactions between the third complementary determining region of the IG heavy chain variable domain (HCDR3) with an epitope in the second framework region (FR2) of either the same smIg or an adjacent smIg. The latter would lead to calcium signaling[15]. (B) Exo-antigen-dependent activation of the BCR in CLL can occur in an antigen-restricted, specific and high-affinity fashion in M-CLL, or in a less restricted, low-affinity fashion (U-CLL). Examples of CLL BCR ligands are given next to each of the red stars, which represent the BCR ligand. BCR signaling in U-CLL is further amplified in the presence of ZAP-70.