Targeting pathological B cell receptor signalling in lymphoid malignancies

Abstract

Signalling through the B cell receptor (BCR) is central to the development and maintenance of B cells. In light of the numerous proliferative and survival pathways activated downstream of the BCR, it comes as no surprise that malignant B cells would co-opt this receptor to promote their own growth and survival. However, direct evidence for BCR signalling in human lymphoma has only come to light recently. Roles for antigen-dependent and antigen-independent, or tonic, BCR signalling have now been described for several different lymphoma subtypes. Furthermore, correlative data implicate antigen-dependent BCR signalling in many other forms of lymphoma. A host of therapeutic agents targeting effectors of the BCR signalling pathway are now in clinical trials and have shown initial success against multiple forms of lymphoma.

Figure 1∣. B cell receptor signalling basics.

Shown are the B cell receptor (BCR), the co-receptor CD19 and various signalling intermediates that are engaged following binding of the BCR to antigen. Several downstream pathways are ultimately triggered, as indicated. The asterisk indicates protein regions affected by recurrent somatic alterations in human lymphomas. See main text for details. BLNK, B-cell linker protein; BTK, Bruton tyrosine kinase; CARD11, caspase recruitment domain-containing protein 11; CBM, CARD11–BCL-10–MALT1; CIN85, Cbl-interacting protein of 85 kDa; DAG, diacylglycerol; IKK, inhibitor of NF-κB kinase; IgH, immunoglobulin heavy chain; IgL, immunoglobulin light chain; IP₃, inositol trisphosphate; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; NFAT, nuclear factor of activated T cells; PI3K, phosphoinositide 3-kinase; PIP₂, phosphatidylinositol-4,5-bisphosphate; PIP₃, phosphatidylinositol-3,4,5-trisphosphate; PKCβ, protein kinase Cβ; PLCγ, phospholipase Cγ; SFK, SRC family kinase.

Figure 2 ∣. Two forms of pathological B cell receptor signalling in lymphoid malignancies.

Chronic active B cell receptor (BCR) signalling, which typifies activated B cell-like diffuse large B cell lymphoma (ABC DLBCL), engages multiple downstream pathways, including nuclear factor-κB (NF-κB). In normal B cells, antigen triggers this form of signalling, and antigen may also have a role in lymphoid malignancies. Tonic BCR signalling, which typifies Burkitt’s lymphoma, engages the phosphoinositide 3-kinase (PI3K) pathway only. Antigen most likely does not contribute to BCR signalling in this context. See main text for details. BTK, Bruton tyrosine kinase; CARD11, caspase recruitment domain-containing protein 11; IgH, immunoglobulin heavy chain; IgL, immunoglobulin light chain; IKK, inhibitor of NF-κB kinase; MALT1, mucosa-associated lymphoid tissue lymphoma translocation protein 1; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPK kinase kinase; mTOR, mammalian target of rapamycin; NFAT, nuclear factor of activated T cells; PKCβ, protein kinase Cβ.