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 displays 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.

Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma

“…BCR activation may be extrinsic or intrinsic via autoantigens or acquired mutations along the signaling pathway. 13 Bruton tyrosine kinase (BTK) is central to the BCR pathway and is thought to play a key role in the survival, proliferation, adhesion, and migration of malignant B cells. [14][15][16][17] Submitted 21 October 2016; accepted 24 January 2017.…”

“…13,18 The development of MZL is often associated with chronic infection (eg, hepatitis C virus, Helicobacter pylori) [19][20][21][22] that may lead to antigen-mediated BCR activation, 21 a potential driver of lymphomagenesis, implicating BTK as a potential target in this malignancy. In a phase 1 trial of single-agent ibrutinib in relapsed/refractory B-cell malignancies, 1 of 3 evaluable patients with MZL had a partial response (PR) and another had stable disease.…”

'Trained immunity: consequences for lymphoid malignancies

“…64 However, B-cells express many other (surface) receptors involved in microbial antigen recognition in addition to the BCR, including CD5 and CD6 (CLL) and pattern recognition receptors like TLR1, TLR2, TLR6, TLR7, TLR9, NOD1 and NOD2 (CLL, NHL). 65,66 Signaling through these receptors is exploited by the malignant cells for their own survival, precisely as shown for BCR activation.…”

Selected miRNA levels are associated with IKZF1 microdeletions in pediatric acute lymphoblastic leukemia

“…It should be emphasized that those two investigated miRNAs (miR-31 and miR-708) negatively influence the NF-κB signaling pathway, which has a role in B-cell receptor activation (49). Aberrant B-cell receptor activation leads to a number of lymphoid malignancies (50). At present, targeted therapies are focused on the inhibition of BCR signaling (51,52).…”