B-Cell Receptor Signaling in Diffuse Large B-Cell lymphoma

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The importance of understanding the genetic and biochemical basis of B-cell receptor (BCR) survival signaling in diffuse large B-cell lymphoma (DLBCL) is underscored by the recent clinical success of agents that target the BCR pathway. DLBCL is composed of multiple distinct molecular subtypes with divergent clinical outcomes. The activated B-cell–like (ABC) subtype is the most aggressive form of DLBCL and is often resistant to standard chemotherapies. ABC DLBCL expresses numerous genes found in antigen-activated B cells, and genetic and pharmacologic studies have demonstrated that ABC DLBCL tumors are addicted to NF-κB activity. The origins of this NF-κB activity remained obscure until RNA interference screens established that the majority of ABC DLBCL cell lines rely on expression of BCR components and downstream signaling effectors for NF-κB activation. Pharmacological inhibition with ibrutinib of Bruton’s tyrosine kinase, a kinase that is required for BCR signaling to engage NF-κB, is selectively toxic for ABC DLBCL tumors; a finding that has now been translated to the clinic. These novel targets not only offer a promising new therapy option for ABC DLBCL, but also demonstrate the value of a deep molecular understanding of oncogenic signaling pathways.

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy representing more than 20,000 new cases each year (http://seer.cancer.gov/statfacts/html/leuks.html). Although DLBCL is commonly described as one disease, gene-expression profiling has identified distinct molecular subtypes. The activated B-cell–like (ABC) and germinal center B cell-like (GCB) subtypes make up the majority of DLBCL cases and are found at roughly equal frequency.1, 2 GCB DLBCL tumors express many genes found in normal germinal center B cells, while gene expression in ABC DLBCL resembles that of antigen-activated B cells. In particular, ABC DLBCL expresses many targets of NF-κB signaling.3 ABC DLBCL has an inferior clinical outcome compared with GCB DLBCL, with an overall survival of ~40%.4 The inability of chemotherapy to eradicate the majority of ABC DLBCL tumors may be because of their constitutive activation of the NF-κB pathway, which is a potent anti-apoptotic mechanism that can blunt the activity of cytotoxic agents.5

Section snippets

Oncogenic NF-κB signaling in ABC DLBCL

ABC DLBCL lines express NF-κB–dependent genes and are addicted to NF-κB activation for their survival. The term “NF-κB” signifies a family of hetero- and homo-dimeric transcriptional activators that are sequestered in the cytoplasm of resting cells, rendering them inert.6 Signals from various activation stimuli converge on IκB kinase (IKK), which phosphorylates the cytoplasmic inhibitor of NF-κB, IκBα, resulting in its degradation. This releases the NF-κB factors to translocate to the nucleus,

Transcriptional feedback

NF-κB activation is frequently depicted as the terminus of multiple prosurvival signaling pathways.6 However, in ABC DLBCL, activation of NF-κB is better described as an amplification of upstream oncogenic signaling because it creates multiple feed-forward and feed-back signaling loops through transcriptional activation of target genes necessary for survival.13 For instance, NF-κB promotes the secretion of IL6 and/or IL10 in most ABC DLBCL.14 These cytokines can interact with cytokine receptors

BCR signaling

Human lymphomas, including DLBCL, retain expression of their BCR even though chromosomal translocations frequently disrupt the IgH locus.19 The BCR is composed of pairs of heavy (IgH) and light (IgL) chains that form a surface-expressed antibody, coupled to a CD79A (Igα) and CD79B (Igβ) heterodimer, which is required for plasma membrane expression, intracellular trafficking, and signal transduction. IgH and IgL are composed of constant regions that are fused to antigen recognition variable

BCR signaling in ABC DLBCL

Although CARD11 mutation represents a bona fide route to transformation in ABC DLBCL, the majority of ABC tumors do not have CBM mutations despite reliance on its presence, suggesting further upstream pathogenic dysfunction. The CBM complex is known to relay signals from the BCR to NF-κB. The role of BCR signaling in ABC DLBCL was first suggested from an RNAi screen, indicating that Btk was critical for tumor survival in ABC lines with wild-type CARD11, but not to GCB lines or an ABC line with

The origins of chronic active BCR signaling

The resemblance of chronic active BCR signaling to antigen-stimulated active BCR signaling in normal B cells raises the possibility that an autoantigen drives BCR clustering and subsequent NF-κB signaling in ABC DLBCL. The potential role of autoantigens in the pathogenesis of chronic lymphocytic leukemia (CLL) has been well studied and is instructive in this regard. BCR signaling has long been suspected as a driver of pro-survival signaling in CLL cells, but it has been difficult to obtain

Cooperation of BCR and MYD88 signaling in ABC DLBCL

The BCR pathway and mutant CARD11 are not the sole sources of NF-κB activity in ABC DLBCL. TLR signaling through the adapter MyD88 is a potent inducer of NF-κB activity in normal immune cells. An RNAi screen revealed that most ABC DLBCL lines are dependent on the expression of MyD88 and its associated signaling kinase, IRAK1.51 Additionally, high-throughput mRNA sequencing of DLBCL samples revealed recurrent mutations affecting the Toll/Interleukin-1 receptor (TIR) domain of MyD88,51 which is

Tonic BCR signaling in lymphoma

Given the required role for tonic BCR signaling in normal B cells, it is not surprising that this survival mechanism is co-opted by some forms of B-cell lymphoma. A prime example is Burkitt lymphoma, an aggressive malignancy derived from the rapidly proliferating germinal center centroblasts (reviewed by Schmitz et al57). An RNAi screen revealed that many Burkitt lymphoma cell lines rely on the BCR for survival, but the majority of these did not require CARD11 and were not dependent on the

BCR pathway inhibitors in ABC DLBCL

The knowledge gained from elucidating the signaling pathways in DLBCL has led to the development of precise therapeutic interventions. Numerous BCR pathway inhibitors have entered the clinic to treat B-cell lymphomas in recent years, targeting kinases proximal to the BCR (e.g., Syk, Btk, and PI3-K), as well as downstream targets such as MALT1 protease activity (reviewed by Young and Staudt62). One of the most promising new agents is the Btk inhibitor ibrutinib, which is an irreversible

Conclusion

Cancer cells utilize a variety of mechanisms to promote their own growth and survival, including subverting cellular signaling networks. Antigen-dependent signaling through the BCR is highly mitogenic, but is a transient and self-limiting response to a foreign antigen in normal B cells. In contrast, ABC DLBCL tumors use a chronic form of active BCR signaling to maintain NF-κB-driven growth and survival signals that promote malignant growth. BCR pathway inhibitors, such as the BTK inhibitor

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    The authors declare that they have no conflicts of interest or competing financial or personal relationships that could inappropriately influence the content of this article.

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