Genetics of diffuse large B-cell lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL), the most frequent subtype of lymphoid malignancy, remains a significant clinical challenge, as ∼30% of patients are not cured. Over the past decade, remarkable progress has been made in the understanding of the pathogenesis of this disease, spurred by the implementation of powerful genomic technologies that enabled the definition of its genetic and epigenetic landscape. These studies have uncovered a multitude of genomic alterations that contribute to the initiation and maintenance of the tumor clone by disrupting biological functions known to be critical for the normal biology of its cells of origin, germinal center B cells. The identified alterations involve epigenetic remodeling, block of differentiation, escape from immune surveillance, and the constitutive activation of several signal transduction pathways. This wealth of new information offers unique opportunities for the development of improved diagnostic and prognostic tools that could help guide the clinical management of DLBCL patients. Furthermore, a number of the mutated genes identified are potentially actionable targets that are currently being explored for the development of novel therapeutic strategies. This review summarizes current knowledge of the most common genetic alterations associated with DLBCL in relation to their functional impact on the malignant transformation process, and discusses their clinical implications for mechanism-based therapeutics.

Figure 1.

Cellular origin and genetic lesions associated with distinct DLBCL subtypes. Schematic representation of the GC reaction, and its relationship with the 2 molecular subtypes of DLBCL NOS, GCB-DLBCL, and ABC-DLBCL (unclassified DLBCL not shown). The most common, functionally characterized genetic alterations identified in this disease (including those shared across different subtypes and those subtype specific) are shown in the bottom panels, where blue indicates loss-of-function events and red indicates gain-of-function events; color codes on the left denote distinct categories, according to the subverted biological pathway. Ag, antigen; Amp, amplifications; D, deletions; FDC, follicular dendritic cells; M, mutations; Tx, chromosomal translocations. Note that, at lower frequencies, mutations affecting CARD11, TNFAIP3, and MYD88 residues other than the L265 hotspot can also be observed in GCB-DLBCL. CREBBP mutations can be found in all subtypes, although frequencies are significantly higher in GCB- (30%) than ABC- (15%) DLBCL. Modified from Pasqualucci and Dalla-Favera with permission.

Figure 2.

CREBBP modulated programs in the GC. CREBBP positively modulates multiple biological programs in the GC, through acetylation of histone and nonhistone proteins (eg, BCL6 and p53) (left). Prominent roles include its ability to regulate antigen presentation/processing via control of CIITA expression, and to counteract the activity of BCL6 by a dual mechanism entailing acetylation-mediated inactivation of its protein and the deposition of H3K27Ac marks on the promoter/enhancer regions of its target genes, which facilitates an active chromatin conformation (bottom panel, with representative cobound genes). This switch may allow the rapid induction of genes that are required for post-GC differentiation in the LZ. CREBBP-modulated programs are disrupted in tumors carrying inactivating mutations of its gene (right). Ac, acetylated lysines.

Figure 3.

Deregulation of BCL6 activity by multiple mechanisms in DLBCL. Recurrent genetic alterations deregulating the function of BCL6 in DLBCL, either directly (by targeting the BCL6 gene) or indirectly (by targeting modulators of its activity). Only representative biological programs suppressed by BCL6 in the GC and disrupted as a consequence of these lesions are shown. Symbols depict loss-of-function (crosses) and gain-of-function (lightning bolt) genetic alterations. Asterisk represents point mutations in the BCL6 regulatory sequences, abrogating DNA binding sites used by the IRF4 transcription factor or by the BCL6 protein itself to negatively regulate BCL6 transcription. Reprinted from Pasqualucci and Dalla-Favera with permission.

Figure 4.

Disrupted signaling pathways in GCB-DLBCL. Genetic lesions preferentially associated with GCB-DLBCL include (i) chromosomal translocations of BCL2 (up to 35% of cases) and/or MYC (∼10% of cases), which lead to their ectopic expression in part by allowing them to bypass BCL6-mediated transcriptional repression; (ii) truncating mutations of the TNFRSF14 receptor, leading to weakened T-cell responses; (iii) gain-of-function mutations of EZH2 (∼20% of cases), which induce transcriptional silencing of various antiproliferative and tumor suppressor genes, including targets common to BCL6 (eg, CDKN1A and BLIMP1); (iv) point mutations in the BCL6 autoregulatory sequences (10% of cases). In addition, loss of PTEN expression is observed in as many as 55% of cases, as a consequence of genetic deletions (15%) and amplifications of miR17-92 (29%), resulting in activation of the PI3K/Akt/mTOR signaling pathway. Targeted agents currently in clinical trial (or, for BCL6, demonstrating activity in preclinical settings) are shown in red.

Figure 5.

Disrupted signaling pathways in ABC-DLBCL. ABC-DLBCL is defined by multiple genetic alterations that fuel malignant transformation by sustaining constitutive NF-κB activity downstream of the BCR and TLR, while blocking terminal B-cell differentiation. Genes directly targeted by these lesions are shown in blue (inactivation) and red (deregulated expression/activity), and symbols at the bottom denote gain-of-function and loss-of-function events. Upstream inhibitors of the BCR, PI3K, and NF-κB signal transduction pathway have shown promising effects in early clinical trials involving ABC-DLBCL patients. Modified from Pasqualucci and Dalla-Favera with permission.