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Review
. 2020 May 28;12(6):1396.
doi: 10.3390/cancers12061396.

Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

Dimitar G Efremov  1 , Sven Turkalj  1 , Luca Laurenti  2
Affiliations
Review

Mechanisms of B Cell Receptor Activation and Responses to B Cell Receptor Inhibitors in B Cell Malignancies

Dimitar G Efremov et al. Cancers (Basel). .

Abstract

The B cell receptor (BCR) pathway has been identified as a potential therapeutic target in a number of common B cell malignancies, including chronic lymphocytic leukemia, diffuse large B cell lymphoma, Burkitt lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone B cell lymphoma, and Waldenstrom's macroglobulinemia. This finding has resulted in the development of numerous drugs that target this pathway, including various inhibitors of the kinases BTK, PI3K, and SYK. Several of these drugs have been approved in recent years for clinical use, resulting in a profound change in the way these diseases are currently being treated. However, the response rates and durability of responses vary largely across the different disease entities, suggesting a different proportion of patients with an activated BCR pathway and different mechanisms of BCR pathway activation. Indeed, several antigen-dependent and antigen-independent mechanisms have recently been described and shown to result in the activation of distinct downstream signaling pathways. The purpose of this review is to provide an overview of the mechanisms responsible for the activation of the BCR pathway in different B cell malignancies and to correlate these mechanisms with clinical responses to treatment with BCR inhibitors.

Keywords: B-cell receptor; BTK; PI3K; SYK; chronic lymphocytic leukemia; lymphoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of B-cell receptor signaling pathways.
Figure 2
Figure 2
B cell development and cell of origin of B cell malignancies covered in this review.
Figure 3
Figure 3
SHP1 expression in different B cell malignancies: (left) Comparison of SHP1 mRNA levels in normal and malignant B cell subsets analysed in dataset GSE2350 (CB, centroblasts; CC, centrocytes; mem. B cell, memory B-cells; HCL, Hairy Cell Leukemia; PEL, Primary Effusion Lymphoma). (right) Comparison of SHP1 expression levels in germinal center B-cell-like (GCB and Activated B cell-like (ABC) diffuse large B cell lymphoma (DLBCL) tumors analysed in dataset GSE4732.
Figure 4
Figure 4
Mechanisms of B cell receptor (BCR) pathway activation in ABC and GCB DLBCL.
See this image and copyright information in PMC

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