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New insights into pre-BCR and BCR signalling with relevance to B cell malignancies

Nature Reviews Immunology volume 13, pages 578–591 (2013)Cite this article

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A Corrigendum to this article was published on 23 August 2013

This article has been updated

Key Points

  • Transformation of early B cells supplants the role of interleukin-7 receptor (IL-7R) and pre-B cell receptor (BCR) signalling.

  • Continual BCR signalling is required for the propagation of many B cell malignancies.

  • The transcription factor forkhead box protein O1 (FOXO1) and the B cell linker protein BLNK have distinct roles in early B cells versus peripheral B cells.

  • The crucial BCR signalling pathways regulated by phosphoinsoitide 3-kinase (PI3K), spleen tyrosine kinase (SYK) and Bruton tyrosine kinase (BTK) are valid therapeutic targets for B cell chronic lymphocytic leukaemia (B-CLL) and B cell non-Hodgkin's lymphoma (B-NHL).

  • Signalling via the BCR is modulated by additional receptors responding to microenvironmental cues.

Abstract

The B cell receptor (BCR) and its precursor (pre-BCR) control B cell homeostasis, differentiation and function. Moreover, aberrant pre-BCR and BCR signalling have a central role in B cell neoplasia; for example, enhanced positive signalling or disrupted negative signalling downstream of the pre-BCR promotes B cell acute lymphocytic leukaemia. The emerging distinctions between tonic and chronic active BCR signalling have contributed to the identification of oncogenic targets downstream of BCR signalling in mature B cell neoplasms. Indeed, the encouraging results of several ongoing clinical trials that target the activity of phosphoinositide 3-kinase δ-isoform (PI3Kδ), Bruton tyrosine kinase (BTK) or spleen tyrosine kinase (SYK) downstream of the BCR highlight the therapeutic potential of inhibiting BCR signalling.

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Figure 1: B cell neoplasms arise at different stages of B cell differentiation.
Figure 2: Perturbed pre-BCR signalling and feedback regulation in B-ALL.
Figure 3: Tonic and chronic active BCR signalling.
Figure 4: Distal BCR signalling.

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Change history

  • 23 August 2013

    In the original version of this article, in the section under the subheading “NF-κB activity in B cell survival and neoplasia” on page 587, reference 97 should also have been included in the following sentence “In ABC-DLBCL, oncogenic amino acid substitutions in the coiled-coiled region of CARMA1 disrupt the intramolecular inhibition that is otherwise mediated by the linker region, which results in the enhanced association of CARMA1 with BCL-10 and in sustained NF-κB activation96 (Fig. 4).” The author apologizes for this error.

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Acknowledgements

The work in the R.C.R.'s laboratory has been supported by US National Institutes of Health (NIH) grants AI041649, HL088686 and AI084883.

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  1. Program on Inflammatory Diseases, Infectious and Inflammatory Diseases Center, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, 92037, California, USA

    Robert C. Rickert

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PowerPoint slides

Glossary

pro-B cells

Cells of the earliest committed stage of B cell development, which is characterized by ongoing immunoglobulin heavy-chain gene rearrangements and a dependence on interleukin-7 receptor signalling.

Large pre-B cells

Cycling (also known as blasting) early B cells that express a functional pre-B cell receptor.

B cell-derived acute lymphocytic leukaemia

(B-ALL). A leukaemia subtype that accounts for the majority of ALL cases and that is derived from the proliferative pro-B cell or pre-B cell compartment in the bone marrow. The genetic basis of B-ALL is usually attributed to the breakpoint cluster region (BCR)–ABL1 translocation or to mutations affecting one or more of the runt-related transcription factor 1 (RUNX1), pre-B cell leukaemia homeobox 1 (PBX1), mixed-lineage leukaemia (MLL), protein tyrosine phosphatase non-receptor type 11 (PTPN11) and RAS genes.

Small pre-B cell stage

A resting stage in which the pre-B cell receptor is down-regulated and recombination activating gene (RAG)-mediated rearrangement of immunoglobulin light-chain genes occurs.

Marginal zone B cells

A mature B cell subset that localizes to the splenic marginal zone and to the area proximal to the marginal sinus.

Germinal centre

A microenvironment of the secondary lymphoid tissues (for example, the spleen, Peyer's patches and lymph nodes) composed of proliferating B cells (which are induced to mutate rearranged variable regions of their heavy-chain and light-chain genes after contact with antigens) and T helper cells. B cells with modified B cell receptors that cannot bind to antigens die by apoptosis, whereas those that bind to antigens are positively selected to exit the germinal centre as memory cells or plasmablasts.

Activation-induced cytidine deaminase

(AID). A B cell-restricted deaminase that can induce double-strand DNA breaks. It is responsible for somatic hypermutation and class-switch recombination.

Class-switch recombination

(CSR). A region-specific recombination process that occurs in activated B cells and results in a change in the class of antibody that is produced. Although the antigen specificity remains the same, the switch in the constant portion of the antibody confers distinct effector properties.

B cell non-Hodgkin's lymphomas

(B-NHLs). A group of B cell malignancies that includes both aggressive (rapidly growing) and indolent (slow-growing) types, such as Burkitt's lymphoma, B cell chronic lymphocytic leukaemia (B-CLL), diffuse large B cell lymphoma, follicular lymphoma, precursor B cell-derived lymphocytic lymphoma and mantle cell lymphoma.

Follicular lymphoma

The most common type of indolent B cell non-Hodgkin's lymphoma. It is characterized by the overexpression of the pro-survival factor B cell lymphoma 2 (BCL-2), which is caused by the translocation of BCL2 into the immunoglobulin heavy-chain locus.

Burkitt's lymphoma

An aggressive type of B cell non-Hodgkin's lymphoma that is characterized by the translocation of MYC into the immunoglobulin heavy-chain locus.

Diffuse large B cell lymphoma

(DLBCL). The most common type of B cell non-Hodgkin's lymphoma in adults, which is composed of the activated B cell (ABC)-derived and the germinal centre B cell (GCB)-derived subtypes. GCB-DLBCL is frequently associated with the constitutive expression of B cell lymphoma 6, whereas ABC-DLBCL is more aggressive and is characterized by chronic active B cell receptor signalling.

B cell chronic lymphocytic leukaemia

(B-CLL). An adult form of B cell leukaemia derived from CD5+ mature or memory B cells. It consists of two subtypes — unmutated and mutated — that are defined by the presence of immunoglobulin mutations, which indicates passage through the germinal centre response. The unmutated subtype is associated with a worse clinical prognosis.

MYC

The oncogene encoding a transcription factor that promotes proliferation, growth and global transcription. Translocation of MYC into the immunoglobulin locus is a hallmark of Burkitt's lymphoma.

Marginal zone lymphoma

(MZL). A group of indolent marginal zone B cell-derived lymphomas that includes splenic marginal zone lymphoma, nodal marginal zone lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (also known as MALT lymphoma). MALT lymphoma can arise as a result of the overexpression of MALT lymphoma translocation protein 1 (MALT1) or the inhibitor of apoptosis protein 2 (IAP2)–MALT1 fusion protein. It can also arise from gastric inflammation caused by chronic Helicobacter pylori infection.

JAK3–STAT5 signalling

The cytokine receptor-associated Janus kinases (JAKs) phosphorylate the signal transducer and activator of transcription (STAT) proteins, which facilitates their dimerization and transport to the nucleus to drive gene transcription.

Forkhead box protein O1

(FOXO1). A member of the FOXO transcription factor family that is negatively regulated by phosphorylation by AKT or serine/threonine protein kinases.

Philadelphia chromosome-expressing B-ALL

(Ph+ B cell acute lymphocytic leukaemia). Leukaemic cells that have the Philadelphia chromosome caused by a translocation and a juxtaposition of the breakpoint cluster region (BCR) and ABL1 genes.

B cell co-receptor molecules

Numerous cell surface molecules that can positively or negatively regulate B cell activation. A subset of these are involved in regulating B cell receptor signalling in the resting state (CD19 and CD22), or following co-recognition of complement-bearing antigens (CD19 and CD21) or immune complexes (CD32).

Class IA PI3K isoforms

Heterodimeric molecules consisting of a 110 kDa catalytic subunit and a smaller regulatory subunit. The catalytic subunits phosphoinositide 3-kinase α-isoform (PI3Kα; also known as p110α) and PI3Kβ (also known as p110β) are ubiquitously expressed, whereas PI3Kδ (also known as p110δ) is expressed primarily in haematopoietic cells. The regulatory subunits prevent the degradation of the catalytic subunit and inhibit its kinase activity, as well as promoting the SH2 domain-dependent recruitment of the holoenzyme to tyrosine-phosphorylated adaptor proteins such as CD19 and B cell adapter for PI3K (BCAP).

B1 cells

A self-renewing subset of mature B cells that predominates in the pleural cavities and that is primarily responsible for the production of natural serum IgM.

MicroRNA

(miRNA). A small RNA molecule that regulates the expression of genes through several mechanisms, including binding to the 3′ untranslated region (3′ UTR) of a target mRNA.

CBM complex

A multienzyme complex consisting of CARD-containing MAGUK protein 1(CARMA1), B cell lymphoma 10 (BCL-10) and mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) that activates nuclear factor-κB following the multimerization and the upstream activation by protein kinase Cβ in B cells.

Inside-out signalling

The process through which intracellular signalling mechanisms result in the activation of cell surface receptors, such as integrins. By contrast, outside-in signalling is the process through which the ligation of cell surface receptors activates signalling pathways inside the cell.

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Rickert, R. New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol 13, 578–591 (2013). https://doi.org/10.1038/nri3487

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