B-cell receptor signaling as a driver of lymphoma development and evolution

Abstract

The B-cell receptor (BCR) is essential for normal B-cell development and maturation. In an increasing number of B-cell malignancies, BCR signaling is implicated as a pivotal pathway in tumorigenesis. Mechanisms of BCR activation are quite diverse and range from chronic antigenic drive by microbial or viral antigens to autostimulation of B-cells by self-antigens to activating mutations in intracellular components of the BCR pathway. Hepatitis C virus infection can lead to the development of splenic marginal zone lymphoma, while Helicobacter pylori infection is associated with the development of mucosa-associated lymphoid tissue lymphomas. In some of these cases, successful treatment of the infection removes the inciting antigen and results in resolution of the lymphoma. Chronic lymphocytic leukemia has been recognized for decades as a malignancy of auto-reactive B-cells and its clinical course is in part determined by the differential response of the malignant cells to BCR activation. In a number of B-cell malignancies, activating mutations in signal transduction components of the BCR pathway have been identified; prominent examples are activated B-cell-like (ABC) diffuse large B-cell lymphomas (DLBCL) that carry mutations in CD79B and CARD11 and display chronic active BCR signaling resulting in constitutive activation of the NF-κB pathway. Despite considerable heterogeneity in biology and clinical course, many mature B-cell malignancies are highly sensitive to kinase inhibitors that disrupt BCR signaling. Thus, targeted therapy through inhibition of BCR signaling is emerging as a new treatment paradigm for many B-cell malignancies. Here, we review the role of the BCR in the pathogenesis of B-cell malignancies and summarize clinical results of the emerging class of kinase inhibitors that target this pathway.

Keywords: Antigen; B-cell receptor; Ibrutinib; Idelalisib; Lymphoma.

Fig. 1

The B-cell receptor (BCR) and its downstream pathways. The arrow indicates direction of signaling from plasmamembrane towards effectors. Antigen binding or cell autologous interaction activates BCR, resulting in phosphorylation of ITAMs in the cytoplasmic domains of CD79A and CD79B. SYK amplifies the initial signal by autophosphorylation and further phosphorylation of ITAMs (the initial amplifying complex is marked in green). LYN has a double function in initiating and terminating BCR signaling depending on interaction with CD19 (inhibitory molecules marked purple, bifunctional molecules light purple). SYK also activates the PI3K arm of the pathway (marked in yellow). Phosphatidylinositol 4,5-bisphosphate (PIP2) is phosphorylated by PI3K to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3, AXL, and BLNK form a signaling hub that recruits the upper part of the BCR pathway to the plasmamembrane. Inhibitory mechanisms include FcγRIIB that inhibits BCR signaling upon binding to immune complexes at the BCR. SHIP-1 and PTEN phosphatases inhibit the PI3K arm of the pathway by hydrolysis of PIP3. AKT and mTOR relay PI3K activation further to downstream targets and cell cycle regulation. The BTK arm of the pathway (marked in red) is initiated by recruitment of BTK to the plasmamembrane signaling hub. PLCγ2 is activated downstream of BTK, leading to subsequent activation of PKCβ. PKCβ phosphorylates IKK to activate NF-κB transcription factors that regulate gene expression of several survival factors. The complex of CARD11, MALT1, and BCL10 is an important part of the pathway activating NF-κB whereas A20 is a negative regulator of NF-κB. The downstream effectors can be modulated towards the pro-apoptotic NF-AT – ERK arm or the pro-survival NF-κB arm depending on balancing of the signaling cascades. Please see the sections on specific parts of the signaling pathways and activation in B-cell malignancies for further details.

Fig. 2

Different mechanisms of BCR activation by antigen in B-cell malignancies. a) A HCV epitope may activate the BCR in SMZL. b) Helicobacter pylori infection causing antigenic and/or inflammatory drive in gastric MALT lymphoma. c) Stereotypic BCRs in CLL and MCL that recognize autoantigens or common microbial antigens provide an antigenic drive. d) BCR of CLL cells binds to epitope within the same or adjacent BCR, resulting in autostimulation. e) The conservation of a functional BCR in FL despite a translocation to the IGH locus is suggestive of a role for BCR activation. Indeed, a fourth of FL specimens have BCRs that recognize self-antigen. Please see text for further details.

Fig. 3

Extrinsic and intrinsic perturbations of BCR signaling in B-cell malignancies a) Chronic active signaling in ABC subtype DLBCL, CARD11 mutations confer BCR independency. b) In MALT lymphomas, overexpression of BCL10 or MALT1 fusion protein results in activation of NF-κB driven proliferation. c) Burkitt’s lymphoma depending on PI3K activity that resembles tonic signaling in resting normal B cells. d) In subsets of DLBCLs, activating mutations of PI3K or loss of inhibitory PTEN induce PI3K driven proliferation. Please see text for further details.

Fig. 4

Multiple event model for B-cell lymphomagenesis. The BCR pathway as depicted in figure 1. Antigenic drive is considered as an initiating event (green). Mutations within the CD79B part of the BCR that increase the response to antigenic drive (blue). Activating mutations (red) and loss of function mutations (yellow) in downstream signal transduction components may confer antigen independent pro-survival signaling and are considered tertiary events. Please see text and figure 2-3 for details on which events are implicated in which types of B-cell malignancies.