The genetic basis of diffuse large B-cell lymphoma

Abstract

Purpose of review: Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease featuring heterogeneous genetic, phenotypic, and clinical characteristics. Understanding the basis for this heterogeneity represents a critical step toward further progress in the management of this disease, which remains a clinical challenge in approximately one-third of patients. This review summarizes current knowledge about the molecular pathogenesis of DLBCL, and describes how recent advances in the genomic characterization of this cancer have provided new insights into its biology, revealing several potential targets for improved diagnosis and therapy.

Recent findings: In the past few years, the development of high-resolution technologies has provided significant help in identifying genetic lesions and/or disrupted signaling pathways that are required for DLBCL initiation and progression. These studies uncovered the involvement of cellular programs that had not been previously appreciated, including histone/chromatin remodeling and immune recognition. Alterations in these pathways could favor epigenetic reprogramming and escape from cellular immunity.

Summary: The identification of genetic alterations that contribute to the malignant transformation of a B cell into a DLBCL is helping to better understand the biology of this disease and to identify critical nodes driving tumor progression or resistance to therapy. The rapid pace at which these discoveries are taking place is poised to have significant impact for patient stratification based on molecular predictors and for the development of rational targeted therapies.

Figure 1. Postulated normal counterpart of major DLBCL subtypes

Schematic cartoon of the GC reaction, illustrating its relationship with major DLBCL subtypes. GCB-DLBCLs display phenotypic similarities with proliferating centroblasts, while ABC-DLBCLs appear to be related to a plasmablastc B cell; PMBCL is postulated to arise from a post-GC B cells in the thymic medulla. The most common genetic lesions that are associated with individual molecular subtypes, or shared by multiple subtypes, are indicated below.

Figure 2. Deregulation of the BCL6-p53 axis by inactivating mutations of CREBBP/EP300

In normal B cells, CBP-mediated acetylation of BCL6 leads to inactivation of its transrepression function, while the same post-translational modification represents an essential requirement for activation of the p53 tumor suppressor functions (left panel). TP53 is also a direct target of BCL6 transcriptional repression in GC B cells, a mechanism that allows the execution of DNA remodeling events such as CSR and SHM, without eliciting DNA damage responses. This fine balance is disrupted in nearly one third of DLBCL, owing to the presence of mutations and/or deletions in CREBBP and, less frequently, EP300 (right panel). Deregulation of the BCL6 oncoprotein and impairment of the p53 tumor suppressor function represent two of presumably many mechanisms by which CREBBP/EP300 genetic lesions contribute to DLBCL transformation.

Figure 3. Pathway lesions in ABC-DLBCL

Schematic representation of a GC centrocyte, expressing a functional surface BCR, CD40 receptor and TLR/IL-1R. Engagement of these signaling cascades in normal B cells converge on the activation of the NF-κB transcription complex, and induces the expression of hundreds of targets genes, including IRF4 and the NF-κB negative regulator TNFAIP3/A20. IRF4, in turn, downregulates BCL6 expression, allowing the release of the plasma cell master regulator PRDM1 and the development into a differentiated plasma cell. In DLBCL, a variety of genetic lesions disrupt this circuit at multiple levels specifically in the ABC-subtype, and contribute to lymphomagenesis by favoring the anti-apoptotic function of NF-κB while blocking terminal B cell differentiation. Crosses indicate inactivating mutations/deletions; lightning bolts denote activating mutations. Modified with permission from [12]