Pathogenesis of human B cell lymphomas

Abstract

The mechanisms that drive normal B cell differentiation and activation are frequently subverted by B cell lymphomas for their unlimited growth and survival. B cells are particularly prone to malignant transformation because the machinery used for antibody diversification can cause chromosomal translocations and oncogenic mutations. The advent of functional and structural genomics has greatly accelerated our understanding of oncogenic mechanisms in lymphomagenesis. The signaling pathways that normal B cells utilize to sense antigens are frequently derailed in B cell malignancies, leading to constitutive activation of prosurvival pathways. These malignancies co-opt transcriptional regulatory systems that characterize their normal B cell counterparts and frequently alter epigenetic regulators of chromatin structure and gene expression. These mechanistic insights are ushering in an era of targeted therapies for these cancers based on the principles of pathogenesis.

Figure 1

Summary of clinical, pathological, and molecular characteristics of mature B cell malignancies. (a) The major lymphoma subtypes discussed in this review are listed with their approximate frequency among B cell neoplasms indicated. See text for details. (b) Transcription factor networks in normal and malignant B cells. The most similar normal B cell counterpart for each malignancy is shown. Follicular lymphoma, Burkitt lymphoma, and germinal center B cell–like (GCB) diffuse large B cell lymphoma (DLBCL) have gene expression profiles that resemble those of normal germinal center B cells. A suite of transcription factors are required to generate and/or maintain normal germinal center B cells. These factors control the indicated cellular processes, which favor the proliferation and selection of germinal center B cells bearing B cell receptors (BCRs) with high affinity for antigen while promoting the apoptosis of B cells with low-affinity BCRs. Activated B cell–like (ABC) DLBCL resembles the post-germinal center plasmablast, a normally transient state en route to terminal plasmacytic differentiation. Constitutive NF-κB activity in ABC DLBCL upregulates expression of the transcription factor IRF4, which drives plasmacytic differentiation. Terminal differentiation is blocked at the plasmablast stage in ABC DLBCL by inactivation of the transcription factor Blimp-1 (see text for details).

Figure 1

Summary of clinical, pathological, and molecular characteristics of mature B cell malignancies. (a) The major lymphoma subtypes discussed in this review are listed with their approximate frequency among B cell neoplasms indicated. See text for details. (b) Transcription factor networks in normal and malignant B cells. The most similar normal B cell counterpart for each malignancy is shown. Follicular lymphoma, Burkitt lymphoma, and germinal center B cell–like (GCB) diffuse large B cell lymphoma (DLBCL) have gene expression profiles that resemble those of normal germinal center B cells. A suite of transcription factors are required to generate and/or maintain normal germinal center B cells. These factors control the indicated cellular processes, which favor the proliferation and selection of germinal center B cells bearing B cell receptors (BCRs) with high affinity for antigen while promoting the apoptosis of B cells with low-affinity BCRs. Activated B cell–like (ABC) DLBCL resembles the post-germinal center plasmablast, a normally transient state en route to terminal plasmacytic differentiation. Constitutive NF-κB activity in ABC DLBCL upregulates expression of the transcription factor IRF4, which drives plasmacytic differentiation. Terminal differentiation is blocked at the plasmablast stage in ABC DLBCL by inactivation of the transcription factor Blimp-1 (see text for details).

Figure 2

Summary of the characteristic molecular features of mature B cell malignancies. For each disease, the top panels represent recurrent genetic aberrations (copy number gain/loss, translocation, mutation, DNA methylation) that produce gain-of-function (red) or loss-of-function (blue) phenotypes. The bottom panels illustrate pathways or genes that are critical for the survival, proliferation, or other malignant phenotypes of each cancer subtype. Genes and pathways are classified according to regulatory category and malignant phenotypes as indicated. For abbreviations of lymphoma subtypes, see Figure 1a. Information for this figure was gleaned from the following references: MCL (3, 251, 354), MALT (1, 18), CLL/SLL (5, 134), HCL (333), FL (263, 268, 269, 362), BL (6, 236, 363), GCB (39, 157, 201, 225, 234, 263, 268, 269, 278, 353, 364, 365),ABC (, , , , , , , , , , , , , , ; A. Shaffer & L. Staudt, unpublished observations), PMBL (2), HL (4, 280, 306).

Figure 3

Deregulated intracellular signaling in activated B cell–like (ABC) diffuse large B cell lymphoma (DLBCL). Constitutive activation of the NF-κB pathway promotes survival in ABC DLBCL and can be achieved by several oncogenic mechanisms, as indicated. Survival of ABC DLBCL cells is also sustained by PI(3)K signaling and autocrine IL-6/IL-10 signaling to the JAK/STAT3 pathways. Mutant MYD88 can also stimulate IFN-β production, which may have both autocrine and immunomodulatory function. See text for details.

Figure 4

Recurrent gain-of-function mutations affecting signaling pathways in lymphoma. (a) Activating mutations in the CARD11 coiled-coil (CC) domain. Shown are frequencies of mutations affecting amino acids within the CC domain in DLBCL, gastric lymphoma, and primary central nervous system lymphoma, summarized from References , , , , . (b) Mutations in the B cell receptor (BCR) subunit CD79B in ABC DLBCL. Shown are mutations affecting the first tyrosine of the CD79B immunoreceptor tyrosine-based activation motif (ITAM) signaling module. These mutations are present in 18% of ABC DLBCL tumors, but other mutations or deletions in the CD79B or CD79A ITAM region occur in an additional 3% of cases (not shown) (106). (c) Location of MYD88 mutations acquired by human lymphomas. Shown is the NMR structure of the MYD88 Toll/interleukin-1 receptor (TIR) domain, with the amino acids that are mutated in lymphoma indicated by their side chains (39). The most prevalent mutation, L265P (arrow), is located in the hydrophobic core of this domain. Several other recurrent mutants reside in the B-B loop that is involved in interactions with other TIR domains present in Toll-like receptors (TLRs). See text for details.