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Molecular pathogenesis of diffuse large B-cell lymphoma

Seminars in Diagnostic Pathology, 2, 28, pages 167 - 177

In past years, substantial insight regarding the pathogenesis of diffuse large B-cell lymphoma has been obtained. Particularly, based on gene expression profile analysis, this disease can be classified into distinct phenotypic subgroups and specific transcriptional programs have been identified. New technologies like next-generation whole genome/exome sequencing and genome-wide single nucleotide polymorphism array analysis have revealed novel lesions involved in the pathogenesis of this disease. This review focuses on the diversity of genetic lesions identified in the different subtypes of diffuse large B-cell lymphoma.

Keywords: DLBCL, Genetic lesions, Germinal center.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma (NHL), accounting for approximately 40% of cases. 1 DLBCL is a heterogeneous disease with a highly variable clinical course, currently treated with combinations of immuno- and chemotherapy. Based on gene expression profile analysis, this single diagnostic category can be classified into distinct phenotypic subtypes, differing in molecular and clinical features and reflecting the origin from specific stages of B-cell differentiation during the germinal center (GC) reaction. 2 During the past decade, multiple recurrent genetic alterations associated with DLBCL have been identified. This review will provide a brief summary of the GC reaction as a basis to understand the biological heterogeneity of DLBCL and then focus on individual genetic lesions contributing to the pathogenesis of this disease.

Most DLBCLs derive from GC B cells

The GC is the site where B cells undergo distinct genetic processes to generate high-affinity antibodies ( Figure 1 ). GCs are formed by proliferating B cells in secondary lymphoid tissues upon T-cell-dependent antigen stimulation. Within the dark zone of the GC, which consists of highly proliferating centroblasts (CBs), B cells undergo somatic hypermutation (SHM) of the variable region of the immunoglobulin genes (IgV).3 and 4 This process produces primarily single nucleotide substitutions, but also deletions and duplications in the IgV heavy- and light-chain genes, resulting in the production of antibodies with high affinity for the antigen.3, 4, and 5 SHM can also target a number of non-immunoglobulin genes in normal B cells, for example the 5′ untranslated region of B-cell lymphoma 6 (BCL6).6, 7, and 8 SHM occurs via DNA strand breaks and requires activation-induced cytidine deaminase (AID), which initiates the process by converting deoxycytidines to uracils, thus triggering base-excision repair and, leading to the creation of abasic sites and error-prone DNA synthesis.9, 10, and 11


Figure 1 The germinal center (GC) reaction. Upon T-cell-dependent antigen stimulation, naive B cells migrate to secondary lymphoid organs, differentiate into centroblasts, and proliferate in the dark zone of the GCs. Within the dark zone, centroblasts undergo SHM, which introduces mostly single base-pair changes into the immunoglobulin variable region of the heavy-and light-chain locus, with the aim of increasing their affinity for the antigen. Centroblasts then move to the light zone, where they differentiate into centrocytes and undergo class-switch recombination. T cells and follicular dendritic cells help to rechallenge the centrocytes with the antigen such that cells with a low-affinity immunoglobulin-receptor are eliminated by apoptosis, whereas a subset of centrocytes with high-affinity to the antigen are selected to differentiate further into memory B cells or plasma cells. (Color version of figure is available online at www.semdiagpath.com .)

The initiation and maintenance of the GC is dependent on BCL6, a transcriptional repressor belonging to the BTB/POZ/zinc finger family of transcription factors. BCL6 is essential in the GC reaction, as evidenced by the observation that mice lacking BCL6 cannot form GCs or produce high-affinity antibodies.12 and 13 BCL6 is highly expressed in CBs, where it directly binds to and represses more than 1200 genes, as recently identified through an integrated biochemical, functional, and bioinformatics approach. 14 BCL6 target genes are involved in a variety of signaling pathways that are important for the GC reaction, including: (i) DNA damage response, (ii) apoptosis, (iii) plasma cell differentiation, (iv) B-cell receptor (BCR) signaling, (v) CD40 signaling, (vi) tumor necrosis factor-β (TNF-β) signaling, (vii) interferon signaling, (viii) Toll-like receptor (TLR) signaling, and (ix) WNT signaling, as well as (x) T-cell-mediated activation.14, 15, 16, 17, 18, 19, 20, 21, and 22 Taken together, these data indicate that BCL6 is essential for the rapid proliferation of CBs, while allowing GC B cells to undergo DNA modifications without inducing an unwanted DNA-damage response. Furthermore, BCL6 inhibits the expression of several transcription factors that are essential for plasma cell differentiation.14, 17, 18, 23, and 24

In the light zone of the GC, CBs differentiate into centrocytes, which are rechallenged by the antigen to allow the selection for B cells producing high-affinity antibodies, whereas cells with a low-affinity Ig receptor are eliminated by apoptosis. 25 Furthermore, centrocytes undergo class-switch recombination (CSR), an intrachromosomal DNA recombination event that confers distinct effector functions to the antibodies by changing their immunoglobulin class from IgD and IgM to IgG, IgA, or IgE. 26 CSR occurs via nonhomologous end joining and requires AID.27 and 28 Another critical process that is initiated in the light zone of the GCs is the differentiation of B cells with a high-affinity Ig receptor into effector plasma cells or memory B cells. The downregulation of BCL6 is essential to allow terminal B-cell differentiation and is accomplished in these cells through at least two distinct mechanisms (ie, activation of CD40 and stimulation of the BCR). CD40 activation via CD40 ligand, expressed on CD4+ T cells, leads to nuclear factor (NF)-κB-mediated activation of interferon regulatory factor 4 (IRF4) and subsequent transcriptional silencing of BCL6.29 and 30 The stimulation of the BCR promotes mitogen-activated protein kinase–mediated phosphorylation of BCL6, followed by its ubiquitination and subsequent proteasomal degradation.5, 25, and 31 Downregulation of BCL6, in turn, restores DNA-damage responses, arrests proliferation, and allows for the expression of positive regulatory domain–containing 1 (PRDM1/ BLIMP1), a transcription factor required for plasma cell differentiation.18 and 23

All B-cell NHLs—with the exception of mantle cell and lymphoblastic lymphoma—derive from either GC cells or B cells that have passed through the GC, as indicated by the fact that these lymphomas carry hypermutated IgV genes. 32 In addition, two main mechanisms of genetic lesion in B-NHL (ie, chromosomal translocations and aberrant somatic hypermutation [ASHM]) occur as by-products of AID-dependent DNA remodeling events that take place in the GC. The requirement of AID in GC-derived lymphomagenesis was recently confirmed by analyses of transgenic mice, where it was demonstrated that GC-derived lymphomas do not develop in animals lacking AID. 33

DLBCL subtypes derive from distinct B-cell differentiation stages

DLBCL is remarkably diverse in both clinical presentation and outcome, likely reflecting its pathogenetic and biological heterogeneity. Over the past decade, the use of genome-wide expression profiling (GEP) has not only allowed a better understanding of the molecular mechanisms underlying the development of this disease, but also revealed a number of features associated with an unfavorable clinical outcome.2, 34, 35, 36, 37, and 38 According to similarities to the putative cell of origin, DLBCL can be divided into at least three different groups: (i) GC B-cell like (GCB) DLBCL, which derives from CBs, (ii) activated B-cell like (ABC) DLBCL, which resembles features of plasmablastic B cells committed to terminal B-cell differentiation, and (iii) primary mediastinal large B-cell lymphoma (PMBCL), presumably arising from thymic B cells.36, 39, and 40 However, 15%-30% of DLBCL cannot be classified into any of the above subgroups.2 and 41 The cell-of-origin–based classification has prognostic value because ABC-DLBCL have a poorer overall survival compared with GCB-DLBCL and respond less effectively to current therapeutic regimes, with cure rates of around 40%.35 and 42 Immunohistochemical markers have been demonstrated to be able to discriminate among the individual subgroups, and several of them—CD10, BCL6, MUM1, B-cell lymphoma 2 (BCL2), and cyclin D2—have been demonstrated to be predictive of survival.40 and 43 The combination of CD10, MUM1, and BCL6 can divide DLBCL in GCB-DLBCL and non-GCB-DLBCL with about 80% concordance with the GEP. 40 A combination of five makers—GCTE1, CD10, BCL6, MUM1, and FOXP1—can achieve about 90% concordance with the GEP. 44 In addition to the difference in cell of origin, these subgroups are associated with diverse genetic alterations (see below), suggesting that they depend on distinct oncogenic programs.

A separate classification scheme using gene-set enrichment analyses identified 3 phenotypic subsets characterized by the expression of genes involved in oxidative phosphorylation, BCR signaling, and host inflammatory response. 37 Tumors in the latter subset exhibit increased expression of macrophage/dendritic cell markers, as well as T/NK cell receptor, activation pathway components, complement cascade members and inflammatory mediators, suggesting an increased inflammatory response. 37 In host inflammatory response tumors, an increased number of infiltrating T cells and dendritic cells was observed. Despite the increased immune response, these tumors do not have a favorable clinical outcome. 37

Mechanisms of genetic alteration in DLBCL

Genetic alterations reported in NHLs and in DLBCL in particular include chromosomal translocations, mutations caused by ASHM, sporadic somatic mutations, and copy number alterations, denoted by deletions and amplifications.

Chromosomal translocations in NHLs represent reciprocal and balanced recombination events frequently but not exclusively involving the immunoglobulin locus, with the breakpoint located either in the switch region or in the target region of SHM.45 and 46 With few exceptions, NHL-associated translocations do not lead to gene fusions, but cause dysregulated expression of the target gene. Given its critical function in both CSR and SHM, AID has been suggested to contribute to B-cell lymphomagenesis by facilitating the occurrence of chromosomal translocations and ASHM, as documented in mice.33 and 47

The term ASHM defines a mechanism of genetic lesion resulting from the aberrant activity of the physiological SHM machinery, as strongly suggested by the features of the observed mutations—specifically, the pattern of nucleotide exchanges, the requirement of transcription, and the distribution within 2 kb from the transcription initiation site. 48 By introducing mutations in the 5′ regulatory region of multiple genes, including coding sequences, ASHM is believed to play a major role in lymphomagenesis by causing deregulated expression of the target genes (often represented by proto-oncogenes) or by altering their protein function.48, 49, and 50 ASHM is primarily found in DLBCL, with more than 50% of cases being affected.48 and 51 Among the target genes identified so far are the well-known proto-oncogenes MYC and PIM1. 48

In addition to chromosomal translocations and ASHM, altered gene expression in DLBCL can be caused by copy number alterations or somatic point mutations, analogous to nonlymphoid tumors. With the advent of novel techniques such as genome-wide single nucleotide polymorphism array analysis and next-generation whole exome/genome sequencing analysis, novel lesions are likely to be identified. Recent examples include mutations and deletions of CREBBP and EP300, which result in defective histone and nonhistone protein acetylation in a significant fraction of DLBCL and follicular lymphoma (FL; see below). 52

Genetic lesions associated with GCB-DLBCL

The gene expression pattern of GCB-DLBCL is similar to that of normal GC-B cells. 2 In addition, these tumors retain typical features of normal GC-B cells, such as CSR and SHM. 53 GCB-DLBCLs are characterized by several different genetic alterations ( Table 1 ).

Table 1 Genetic lesions associated with different subtypes of DLBCL

Gene Genetic alteration Functional consequences Biological consequences References
 BCL2 t(14;18)

  • Ectopic BCL2 expression
  • Escape from BCL6-mediated repression
  • Escape from BCL6-mediated repression
Inhibition of apoptosis 54

20 ,  16
  • t(8;14)
  • t(2;8)
  • t(8;22)
  • Ectopic expression
  • Escape from BCL6-mediated repression
Enhanced proliferation and survival 55
 EZH2 Activating mutations Increase in histone H3K27 trimethylation Epigenetic reprogramming 66
 MLL2 Inactivating mutations Decrease in histone H3K4 trimethylation Epigenetic reprogramming 66 ,  67
 MEF2B Point mutations Unknown Unknown 66 ,  67
 CREBBP/EP300 Inactivating mutations/deletions Reduced acetyltransferase activity Epigenetic reprogramming Enhanced BCL6 oncogenic activity Loss of p53 tumor suppressor activity 52
 PTEN Deletions Loss of PIP3 negative regulation Activation of AKT signaling pathway 58
 PIK3CA Activating mutations Increased catalytic activity Activation of AKT signaling pathway 62
  • Mutations of the B6BS
  • t(3;other) (q27;other)
  • Evasion from BCL6 autoregulation
  • Deregulated expression
Enhanced proliferation Resistance to apoptosis Block in differentiation Impaired DNA damage response 49 ,  50
 REL Gene amplification Increased gene dosage Unclear 35
 TNFAIP3 (A20) Biallelic mutations/deletions Loss of NF-κB negative regulation
  • Constitutive NF-κB signaling
  • Enhanced cell survival
 CARD11 Activating mutations Increased NF-κB activation
  • Constitutive NF-κB signaling
  • Enhanced cell survival
 CD79A CD79B Activating mutations
  • Increased BCR expression
  • Reduced activation of Lyn
  • Constitutive NF-κB signaling
  • Enhanced cell survival
 MYD88 Activating mutation Spontaneous assembly and activity of IRAK1/IRAK4 complex
  • Constitutive NF-κB signaling
  • JAK/STAT signaling activation
 BCL6 t(3;other)(q27;other) Deregulated expression Enhanced proliferation Resistance to apoptosis Block in differentiation Impaired DNA damage response 73 ,  91 ,  92
  • Biallelic
  • Mutations/deletions
Loss of PRDM1 function Block in differentiation 103 ,  104 ,  105
 BCL2 Gene amplification Enhanced expression of BCL2 Inhibition of apoptosis 35
 INK4a/ARF Homozygous deletion Loss of function
  • Inhibition of apoptosis
  • Inactivation of the p53 pathway
 JAK2 Gene amplification Increased gene dosage Enhanced proliferation and cellular transformation 119
  •  PDL1
  •  PDL2
Gene amplification Increased gene dosage Evasion of T-cell mediated immune response 38 ,  118
 SOCS1 Homozygous deletion Loss of JAK2 degradation Enhanced JAK2 signaling 121
 TNFAIP3 Mutations/deletions Loss of NF-κB negative regulation
  • Constitutive NF-κB signaling
  • Enhanced cell survival
 REL Gene amplification Increased gene dosage Unclear 115 ,  117

In approximately 35% of cases, the translocation t(14;18) leads to the ectopic expression of the BCL2 oncogene, a key antiapoptotic molecule also expressed in FL and chronic lymphocytic leukemia. 54 BCL2 translocations deregulate BCL2 by juxtaposing potent regulatory elements from the Ig locus in close proximity to the BCL2 locus, as well as by disrupting suppression by BCL6.16 and 20 Additionally, about 40% of DLBCL cases without a t(14;18) translocation coexpress BCL2 and BCL6 as the result of several mechanisms including (i) deregulation of Miz1, the coactivator molecule by which BCL6 binds to the BCL2 promoter; (ii) ASHM of BCL2 promoter sequences, and (iii) mutations in the BCL2 coding sequence. 16 Increased levels of BCL2 have been associated with an inferior outcome in DLBCL.55 and 56

In 15% of DLBCL, the MYC gene, encoding for a transcription factor associated with Burkitt's lymphoma, is deregulated because of chromosomal translocations—most commonly t(8;14)—which bring the MYC coding sequence under the control of the immunoglobulin promoter/enhancer.55 and 57 Amplifications of the MIGH1 region containing the microRNA (miR) 17-92 cluster on chromosome 13q have been reported in approximately 12% of GCB-DLBCL. 58 This miR polycistron acts as a potential oncogene and accelerates MYC-induced lymphomagenesis in mice.59 and 60 Furthermore, the miR-17-92 cluster may enhance oncogenesis by increasing proliferation and survival via inhibition of the tumor suppressor PTEN and the proapoptotic protein BIM. 60 Interestingly, deletions of PTEN on chromosome 10q, which are reported in approximately 11% of cases and lead to the activation of AKT, are more frequent in GCB-DLBCL than in ABC-DLBCL and are mutually exclusive with amplifications involving the miR-17-92 cluster.58 and 61 Additionally, activation of phosphatidylinositol 3-kinase (PI3K) by mutations can trigger AKT and other pathways that inhibit apoptosis and promote cellular growth, cell motility, and angiogenesis. Mutations in PIK3CA are reported in approximately 8% of DLBCL and are mutually exclusive with loss of PTEN. 62

A number of chromatin-modifying genes have been reported to be mutated in DLBCL with a prevalence in GCB-DLBCL. Recurrent somatic mutations affecting a single residue in the polycomb-group oncogene EZH2 have been found in 21.7% of GCB-DLBCL. 63 EZH2 is part of the polycomb repressive complex and encodes for a histone methyltransferase that methylates Lys27 of histone H3. The identified mutations result in the replacement of a single tyrosine within the EZH2 SET domain and have been recently demonstrated to enhance the ability of EZH2 to trimethylate histone H3, in part by increasing its affinity for the substrate.63, 64, and 65 The histone methyltransferase MLL2 is somatically mutated in approximately 30% of DLBCL. Most of the mutations introduce premature stop codons and frameshift insertions and deletions that most likely inactivate MLL266 and 67 (and unpublished data). Another recently identified target is myocyte enhancer factor 2B (MEF2B), a member of the MADS/MEF2 family of DNA binding proteins that cooperates with histone-modifying enzymes to regulate the expression of genes. MEF2B is mutated in approximately 9% of DLBCL66 and 67 (and unpublished data). A recent study has identified monoallelic deletions and mutations inactivating CREBBP and EP300 in nearly 39% of GCB-DLBCL and less frequently in ABC-DLBCL (17% of samples). 52 CREBBP and EP300 are acetyltransferases that act as transcriptional coactivators in multiple signaling pathways. As a consequence of the mutations, CREBBP/EP300 lose their ability to acetylate BCL6 and p53. This posttranslational modification inactivates BCL6 by disrupting the recruitment of histone deacetylases (HDACs), thus hindering its capacity to repress transcription, while represents an essential requirement for p53 activation.68 and 69 Thus, mutations of CREBBP and EP300 may contribute to lymphomagenesis by favoring the decreased activity of the tumor suppressor and the constitutive activation of the oncogene. 52 Interestingly, these mutations are also reported in approximately 40% of FL, suggesting that DLBCL and FL share common pathogenetic events. 52

Mutations of p53 have been associated with transformation from FL and should thus be more frequent in GCB-DLBCL, although conflicting results have been reported. Nevertheless, p53 mutations were able to stratify GCB-DLBCL patients in subgroups with different survival.70, 71, and 72

Mutations of the BCL6 5′ regulatory region are reported in approximately 75% of all DLBCLs and reflect the activity of the physiological SHM mechanism operating in GC B cells.7 and 8 However, a subset of these mutations affecting the gene 5′ untranslated exon 1 were exclusively found in DLBCL—particularly in GCB-DLBCL—where they impair a negative autoregulatory loop through which BCL6 controls its own expression.49 and 73

Evidence of ASHM is observed in GCB-DLBCL as well as in ABC-DLBCL, overall accounting for more than 50% of patients. 48 However, different mutation frequencies have been observed at certain target genes in the two DLBCL phenotypic subtypes. Of note, MYC and BCL2 are preferentially targeted by ASHM in GCB-DLBCL. 16

Genetic lesions associated with ABC-DLBCL

The ABC subtype of DLBCL has a gene expression pattern that is similar to that of normal B cells activated in vitro by BCR cross-linking and to a subset of GC B cells committed to plasma cell differentiation. 2 A prominent feature of the ABC-DLBCL gene expression signature is the enrichment in NF-κB target genes, suggesting that constitutive activation of NF-κB plays an important role in this disease subtype.74 and 75 Indeed, the NF- B transcription complex is present in the nuclei of the tumor cells in a large fraction of cases, and ABC-DLBCL cell lines are specifically dependent on NF-κB activity because interference with NF-κB signaling kills ABC-but not GCB-DLBCL.74 and 76 Constitutive NF-κB activation can be the result of several distinct genetic alterations, which affect both positive and negative regulators of the pathway predominantly in ABC-DLBCL ( Figure 2 and Table 1 ).75, 77, 78, and 79 One of the most commonly involved genes is TNFAIP3, encoding for the negative NF-κB regulator A20, with approximately 30% of cases displaying biallelic inactivation by mutations and/or deletions. 77 A20 is a dual-function ubiquitin-modifying enzyme involved in the termination of NF-κB responses. 80 Consistently, enforced expression of A20 in DLBCL cell lines carrying biallelic TNFAIP3 inactivation induced cell growth arrest and apoptosis by blocking NF-κB signaling, as demonstrated by the cytoplasmic relocation of p50.77 and 81 Genetic alterations of A20 are also present in other lymphomas characterized by constitutive NF-κB activation (eg, marginal zone lymphoma, Hodgkin's lymphoma), while they are less common in GCB-DLBCL.77, 81, 82, and 83


Figure 2 Oncogenic pathways in ABC-DLBCL. The stimulation of several surface receptors, including the BCR, CD40, and Toll-like receptors, triggers signaling cascades resulting in the activation of the NF-κB pathway. In ABC-DLBCL, NF-κB is constitutively activated and several genetic lesions that contribute to this activation have been identified. (Color version of figure is available online at www.semdiagpath.com .)

In normal B cells, BCR-induced activation of NF-κB requires CARD11, a scaffold protein that coordinates the activation of IκB kinase β. 84 Mutations of CARD11 are reported in approximately 10% of ABC-DLBCL as well as in a smaller subset of GCB-DLBCL and typically affect amino acids within or adjacent to the coiled-coil domain.77 and 85 Introduction of CARD11 mutants into lymphoma cell lines leads to constitutive NF-κB activation, suggesting that lymphoma cells with CARD11 mutations are engaging the NF-κB pathway in the absence of BCR signaling. 85 CD79A and CD79B are proximal BCR subunits and were demonstrated to be mutated in approximately 20% of ABC-DLBCL. 74 The mutations target the immunoreceptor tyrosine-based activation motif (ITAM) of CD79A and CD79B, most frequently at a conserved tyrosine residue, thus increasing surface BCR expression and attenuating a feedback inhibitor of BCR signaling. 74 Overall, CD79A and CD79B mutations are thought to induce chronic active BCR signaling, with consequent activation of NF-κB, PI3K, and MAP-kinase pathways.

During the normal immune response, NF-κB is also activated after stimulation of TLRs and receptors for interleukin (IL)-1 and -8.86 and 87 MYD88 functions as a signaling adapter protein, coordinating the assembly of a complex that activates NF-κB following TLRs and IL-1 and IL-8 receptor stimulation.86 and 87 MYD88 mutations are reported in approximately 30% of ABC-DLBCL, harboring the same amino acid substitution (L265P) in the Toll/IL-1 receptor domain. 78 The L265P mutant protein may promote cell survival by activating NF-κB signaling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10, and INFβ. 78

Other mutations affecting NF-κB modulators in DLBCL include TRAF2 (3%), TRAF5 (5%), MAP3K7 (5%), and RANK (8%), 77 A TRAF2 mutant isolated from an ABC-DLBCL was able to activate NF-κB, although the functional consequences of the remaining mutations have not been studied in detail. 77

Consistent with these findings, treatment with the proteasome inhibitor bortezomib, which blocks the degradation of IκBα, leads to significantly higher response rates in ABC-DLBCL patients. 88

Normal GC B cells require the downregulation of BCL6—mediated by NF-κB—and expression of IRF4, BLIMP1, and XBP1 for plasma cell differentiation.17, 18, and 24 In ABC-DLBCL, several lesions involving this pathway have been reported. Chromosomal translocations of BCL6, located on chromosome 3q27, are detected in approximately 35% of cases, with a 2-fold higher incidence in ABC-DLBCL compared with GCB-DLBCL.73, 89, 90, and 91 The translocations are balanced and reciprocal and involve various alternative partners.12, 91, 92, 93, and 94 Most of the translocations result in a fusion transcript, with the promoter region and the first noncoding exon of BCL6 being replaced by the regulatory region of the translocation partner.95 and 96 The most common translocations involve the immunoglobulin heavy-chain promoter, resulting in constitutive expression of BCL6.12 and 91 Deregulated expression of BCL6 is thought to play a critical role in blocking differentiation, decreasing the p53-mediated apoptotic response to DNA damage and providing a proliferative advantage.14, 15, 17, 18, 19, and 20 This model is supported by the fact that mice with deregulated BCL6 expression develop DLBCL. 97

The PRDM1 gene—located on chromosome 6q21—encodes for BLIMP1, a zinc finger transcriptional repressor. BLIMP1 is essential for the differentiation of B cells into plasma cells, which it promotes in part by repressing genes involved in BCR signaling and proliferation.98, 99, 100, 101, and 102 Inactivating mutations and deletions of PRDM1 are reported in up to 30% of ABC-DLBCL.103, 104, 105, and 106 Additionally, BLIMP1 can be inactivated by transcriptional repression through constitutively active BCL6, as is the case in patients carrying BCL6 translocations. Consistent with this model, chromosomal translocations of BCL6 and genetic alterations affecting BLIMP1 are mutually exclusive.103, 104, and 105 Notably, the remaining over 30% of ABC-DLBCL lack BLIMP1 protein despite the expression of IRF4 and the absence of genetic alterations in BLIMP1 or BCL6. 105 Because IRF4 is invariably coexpressed with BLIMP1 in differentiating GC B cells and plasma cells, these observations suggest that alternative mechanisms exist to inactivate BLIMP1 in ABC-DLBCL. The role of BLIMP1 as a tumor suppressor has been recently demonstrated in a mouse model where conditional deletion of the gene leads to the development of lymphoproliferative disorders recapitulating features of ABC-DLBCL.105 and 106

Amplifications of the telomeric segment of chromosome 19q are reported in approximately 25% of ABC-DLBCL. 58 SPIB—an ETS family transcription factor—is supposed to be one functionally important gene in this region, a hypothesis supported by the fact that downregulation of SPIB was toxic to ABC-DLBCL cell lines. 58 In addition, a translocation between SPIB and the Ig heavy chain locus was found in one ABC-DLBCL cell line. 46

Homozygous or heterozygous deletions of the INK4a/ARF locus are observed in approximately 30% of ABC-DLBCL. 58 P16INK4a and p14ARF regulate the pRB and the p53 tumor suppressor pathways, and inactivation of the p53 pathway via INK4a/ARF is reported to inhibit apoptosis in aggressive lymphoid malignancies.107 and 108

Genetic lesions associated with PMBCL

PMBCL accounts for less than 3% of NHLs and is mostly observed in young adults with a median age of about 35 years.109 and 110 Females are affected more frequently than males. 111 The only site of lymphoma involvement is the anterior mediastinum, but the rapidly growing bulky tumor can extend locally into other thoracic structures. 112 This distinctive location, together with its gene expression profile, suggest that this DLBCL subtype arises from thymic B cells in the mediastinum.111, 113, and 114 PMBCLs are characterized by several genetic alterations ( Table 1 ). A common lesion is represented by gains of band 9p24, reported in approximately 70% of cases.115, 116, and 117 The amplified region contains several genes of possible pathogenetic significance, including the gene encoding for the tyrosine kinase JAK2 and the PDL1 and PDL2 loci, which encode for regulators of T-cell responses. These three genes were all expressed at high levels in PMBCL compared with other DLBCL subtypes. 38 Recently, PDL1 and PDL2 have been identified as key targets of these amplifications using high-resolution copy number analysis. 118 Overexpression of JAK2 was proposed to be responsible for the constitutive activation of the transcription factor STAT6 because of its ability to activate IL-3 and IL-4, which are both involved in the regulation of STAT6.36 and 119 Interestingly, SOCS1, a negative regulator of JAK2, is also commonly affected by inactivating genetic lesions in PMBCL.120 and 121

PMBCL shares with ABC-DLBCL the evidence of constitutive NF-κB pathway activation, being characterized by the increased expression levels of NF-κB targets that promote cell survival and inhibit apoptosis. 122 Gains of chromosome 2p14-16 encompassing the NF-κB family member REL are reported in approximately 70% of PMBCL.115 and 117 Also affected by these gains is BCL11A, a transcriptional repressor that may provide a survival advantage. 117

Interestingly, PMBCL and classic Hodgkin's lymphoma have a notable genomic similarity, both harboring frequent gains on 2p and 9p. 123 Furthermore, remarkable similarities in the gene expression profiles of these two diseases have been reported.36 and 38 However, the gene expression signature of PMBCL retains the expression of genes typical of mature B cells, whereas these transcripts are shut down in Hodgkin's lymphoma.

Concluding remarks

Within recent years our understanding of the pathogenesis of DLBCL has significantly improved. Genome-wide expression profiling has illustrated the heterogeneity of DLBCL and allowed a better understanding of the molecular mechanisms underlying the disease. The known genetic lesions do not account for all DLBCL cases and therefore represent only a subset of those required for tumor initiation. New techniques like whole genome/exome sequencing and genome-wide single nucleotide polymorphism analyses have already led to the identification of novel genetically altered genes in DLBCL and further improved our understanding of the disease. The identification of tumors that are dependent on particular signaling pathways is essential to improve disease stratification and will provide the basis for more effective and less toxic targeted therapeutic approaches.


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a Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York

b Department of Clinical Pathology and Cell Biology, Columbia University, New York, New York

c Department of Genetics and Development, Columbia University, New York, New York

lowast Address reprint requests and correspondence: Riccardo Dalla-Favera, MD, Department of Genetics and Development, Columbia University, 1130 St. Nicholas Avenue, New York, NY 10032