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Combating the epigenome: epigenetic drugs against non-Hodgkin’s lymphoma

Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria

^‡Authors contributed equally

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Ana-Iris Schiefer^‡

Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria

^‡Authors contributed equally

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Gerda Egger

* Author for correspondence

Clinical Institute of Pathology, Medical University of Vienna, Waehringer Guertel 18–20, 1090 Vienna, Austria.

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Email the corresponding author at gerda.egger@meduniwien.ac.at

Published Online:29 Jul 2013https://doi.org/10.2217/epi.13.39

Abstract

Non-Hodgkin’s lymphomas (NHLs) comprise a large and diverse group of neoplasms of lymphocyte origin with heterogeneous molecular features and clinical manifestations. Current therapies are based on standard chemotherapy, immunotherapy, radiation or stem cell transplantation. The discovery of recurrent mutations in epigenetic enzymes, such as chromatin modifiers and DNA methyltransferases, has provided researchers with a rationale to develop novel inhibitors targeting these enzymes. Several clinical and preclinical studies have demonstrated the efficacy of epigenetic drugs in NHL therapy and a few specific inhibitors have already been approved for clinical use. Here, we provide an overview of current NHL classification and a review of the present literature describing epigenetic alterations in NHL, including a summary of different epigenetic drugs, and their use in preclinical and clinical studies.

Keywords:

**Figure 1. Major non-Hodgkin’s lymphoma subtypes with known origins from different regions within the lymph node.**
Formalin-fixed paraffin-embedded sections of a normal lymph node (center, round shape) and different non-Hodgkin’s lymphomas originating from various cell populations of the node (rectangular images). Tumor tissues are shown by hematoxylin and eosin staining, Giemsa staining (left image) or specific immunohistochemical staining for proteins that are used for routine clinical classification (brown/red staining in right image). Note that B-cell lymphomas originate from the GC, MZ and MGZ, whereas T-cell lymphomas are descendants of the PC.
AILT: Angioimmunoblastic T-cell lymphoma; ALCL: Anaplastic large-cell lymphoma; BL: Burkitt’s lymphoma; DLBCL: Diffuse large B-cell lymphoma; FL: Follicular lymphoma; GC: Germinal center; MCL: Mantle cell lymphoma; MGZ: Marginal zone; MZ: Mantle zone; MZL: Marginal zone lymphoma; PC: Paracortex; PTCL-NOS: Peripheral T-cell lymphoma not otherwise specified.

**Figure 2. Alterations of chromatin states in non-Hodgkin’s lymphoma due to mutations in chromatin-related proteins.**
Mutations in or deregulation of PcG proteins, HATs/HMTs, HDACs, CRCs and DNMTs are frequently found in non-Hodgkin’s lymphoma and result in changes of chromatin states and gene expression. Major epigenetic changes involve *de novo* PcG silencing (top left), *de novo* DNA methylation (top right), epigenetic switching (lower left) or targeted repression (lower right). Active chromatin (red) contains nucleosomes (cylinders) that are decorated with active histone marks (H3ac global, H4ac global, H3K4me3 and H3K27ac), whereas repressive chromatin (blue) is marked by repressive histone modifications (H3K27me3 and H2AK119ub1) or methylated DNA (black circles, 5mC). Black arrows indicate active genes, green arrows indicate gain of function and the red X indicates loss of function. Note that repressed chromatin also contains nucleosomes at their transcription start sites, whereas active genes are nucleosome depleted.
CRC: Chromatin remodeler; DNMT: DNA methyltransferase; HAT: Histone acetyltransferase; HDAC: Histone deacetylase; HMT: Histone meythltransferase; PcG: Polycomb group; TF: Transcription factor.

Classification of non-Hodgkin’s lymphoma based on clinical & molecular parameters

Non-Hodgkin’s lymphomas (NHLs) comprise a heterogeneous group of lymphoid neoplasms that originate from either mature or immature B cells, T cells or natural killer cells (Table 1). The incidence of lymphoma is still increasing worldwide and encompasses 33.65 cases per 100,000 individuals per year [1]. NHLs constitute 4% of all cancers and are more common in developed countries, especially in the USA, Australia and western Europe.

Lymphomas are classified according to the WHO classification of lymphoid neoplasms. This classification succeeded the Revised European–American Classification of Lymphoid Neoplasms [2] – the first worldwide consensus on lymphoma classification – in 2001 and was finally updated in 2008 [3]. The classification incorporates histomorphology, immunophenotype, and genetic, molecular and clinical features.

Many NHLs resemble normal B and T cells at diverse stages of differentiation and maturation, so they can be stratified according to their cell line derivation and to the stage of differentiation at which lymphoma transformation occurred (Figure 1)[3]. Within the B-cell line, lymphocyte differentiation begins in the bone marrow with progenitor B cells. They undergo immunoglobulin VDJ heavy chain, followed by VJ light-chain gene rearrangement and emerge as pre-B cells with intracytoplasmic µ-heavy chains, followed by surface immunoglobulin-positive immature IgM⁺ B cells and IgM⁺ IgD⁺ naive B cells. Corresponding lymphomas of early differentiation are B-lymphoblastic lymphomas resembling B-cell progenitors, mantle cell lymphomas (MCLs) and a subset of chronic lymphocytic leukemia with wild-type IGHV genes, which are believed to derive from CD5⁺ naive B cells and CD5⁺ pregerminal center mature B cells [4] within the lymph node. After antigen exposure, naive B cells mature in a T cell-independent way directly into IgM-secreting plasma cells, or they colonize primary follicles in the lymph node and differentiate into germinal center centroblasts. Within the germinal center, somatic hypermutation in the immunoglobulin heavy- and light-chain variable region genes occurs to improve antigen affinity. Germinal center-derived lymphomas have mutated IgV genes and comprise follicular lymphoma (FL), Burkitt’s lymphoma (BL), a portion of diffuse large B-cell lymphoma (DLBCL) and Hodgkin’s lymphoma. Centroblasts mature further to centrocytes, which differentiate into either memory B cells or plasma cells. Marginal zone lymphoma, lymphoplasmacytic lymphoma, chronic lymphocytic leukemia with somatic IGHV mutation, some DLBCL and plasma cell myeloma are lymphoid neoplasms corresponding to postgerminal center cells.

T cells arise from progenitor T cells in the bone marrow and mature during migration through the thymus to become either CD4⁺ or CD8⁺ single positive T cells via double-negative cortical (CD4^- and CD8^-) and double-positive thymocytes (CD4⁺ and CD8⁺) [3]. T-cell receptor gene rearrangement takes place within the subcapsular and outer cortex of the thymus. Structural differences in the T-cell receptor allow the distinction of αβ- and γδ-T cells. The latter belong to the innate immune system and only comprise a very small subset of T cells that solely colonize extranodal sites, such as the splenic red pulp, intestinal epithelium, skin or other epithelial sites. This anatomical distribution is also reflected by the corresponding sites of involvement of γδ-T-cell lymphomas, which arise from their normal cell counterparts. By contrast, T-cell lymphomas derived from αβ-T cells are mainly of nodal origin. With a few exceptions, such as angioimmunoblastic T-cell lymphoma, the follicular variant of T-cell lymphoma, and adult T-cell leukemia/lymphoma, which were linked to follicular T-helper cells [5,6] and regulatory T cells [7], respectively. There is limited knowledge of the normal cellular counterparts within this group, so most nodal T-cell lymphomas still remain under a broad category of peripheral T-cell lymphoma ‘not otherwise specified’ (PTCL-NOS) [2].

Increased incidence of lymphoma is observed in patients with an altered immune system, either owing to an autoimmune disease or immunodeficiency caused by infection with HIV, iatrogenic immunosuppression or congenital immune deficiency syndromes [8–10]. Host defects in immune regulation, chronic viral infections and genetic alterations are believed to be the lymphoma driving factors.

Several viral infections, such as Epstein–Barr virus [11], human herpesvirus-8 [12], human T-cell lymphoma/leukemia virus type 1 [13] and hepatitis C [14], can cause lymphoma development due to chronic antigen stimulation and, in the cases of Epstein–Barr virus, human herpesvirus-8 and T-cell lymphoma/leukemia virus type 1, due to the oncogenic properties of the virus-encoded proteins expressed by the affected lymphocytes. In some B-cell neoplasms, especially mucosa-associated lymphoid tissue (MALT) lymphomas, lymphomagenesis can be attributed to bacteria or the immune response to bacterial antigens such as Helicobacter pylori, Borrelia burgdorferi, Chlamydia psittaci, Chlamydia pneumoniae, Chlamydia trachomatis and Campylobacter jejuni[15].

NHL can involve nodal and extranodal sites. Tumor cells can spread into the lymph nodes, spleen, liver, bone marrow, skin and other organs. Since individual lymphomas differ in clinical features according to the involved organ, the site-specific impact is recognized in the current WHO classification [3]. The extent of lymphoma spread is specified by the Ann Arbor staging system [16]. Required staging analyses encompass imaging analysis, such as chest x-ray, computed tomography, MRI of the chest, abdomen and pelvis, biopsy of bone marrow and blood tests. F-fluorodeoxyglucose PET is a sensitive imaging method in staging and monitoring early therapeutic response. Clinical outcome and prognosis is predicted by the International Prognostic Index (IPI), which defines the four risk groups: low, low-intermediate, high-intermediate and high risk; incorporating five independently significant risk factors associated with survival: age, tumor stage, number of extranodal sites of disease, performance status and serum lactate dehydrogenase level [17].

Lymphomagenesis can be caused by alterations in the DNA sequence due to chromosomal translocation, mutation, deletion or gain of genetic material. Characteristic reciprocal translocations have been identified in some mature B-cell lymphomas [18]. Most of them involve the immunoglobulin heavy-chain gene locus on 14q32 and a functional proto-oncogene as a translocation partner, which becomes constitutively expressed due to its transcriptional activation by the immunoglobulin heavy-chain gene promoter. Examples are the translocation t(14;18)(q32;q21) in FL, which leads to a rearrangement and upregulation of the antiapoptotic protein BCL2. The IgH/cyclin D1 translocation t(11;14)(q13;q32) is the hallmark of MCL and exhibits its pro-proliferative properties through inhibition of cell cycle regulators RB1 and p27kip1 [19,20]. Recently, attention has been paid to ‘early lesions’ and early manifestations of lymphoma, such as FL or MCL in situ, which are characterized by a clonal population with the hallmark t(14;18) or t(11;14), respectively, but in which the neoplastic cells remain restricted to their ‘normal anatomic’ distribution [21,22]. Other recurrent IgH translocations are the t(8;14)(q24;q32) in BL, which leads to overexpression of the MYC oncogene, and the t(1;14) in MALT lymphoma, involving the BCL10 oncogene [18,23,24]. Another mechanism leading to oncogenic transformation and caused by translocation is the generation of a transcriptionally active chimeric fusion gene with oncogenic potential such as the API2/MALT1 fusion gene in MALT lymphoma generated by t(11;18) or the NPM/ALK fusion gene in ALK⁺ anaplastic large-cell lymphoma (ALCL) caused by t(2;5). In T-cell lymphomas, only very few specific genetic alterations, excluding the t(2;5) translocation, have been identified so far. DNA microarray technology provides new insights into candidate genes that are critical for lymphomagenesis and enables genetic molecular profiling. Thus, lymphomas can be further grouped according to their molecular signature (Table 1). A hierarchical clustering algorithm of 100 differently expressed genes enabled the definition of two principal molecular subtypes within the biological heterogeneous entity of DLBCLs; the germinal center B cells (GCB) and activated B-cell subtypes, respectively. These subtypes are associated with specific genetic alterations, different molecular signaling pathways and differences in clinical outcome [25].

To date, gene expression profiling in T-cell lymphomas has failed to define more subtypes; however, it has provided predictive information about the response to novel therapeutic targets [26,27].

Disruption of chromatin biology in NHL

The induction of malignant processes in B- and T-lineage cells, leading to the development of NHL, can derive from a multitude of genetic and cellular alterations, such as genomic translocations [18], integration and (re)expression of viral DNA [28], and mutations in context-specific oncogenes or tumor suppressors [25]. However, recently it has become increasingly clear that major changes in chromatin and chromatin-modifying enzymes are also frequently detected in NHL and contribute to disease progression (Figure 2), thus providing a rationale for the development of drugs targeting these enzymes.

HDACs are members of a large family of chromatin-modifying proteins, whose deregulated expression or recruitment to chromatin has been observed in numerous cancers [29]. HDACs are enzymes that remove acetyl groups from lysines on histones or other substrates, which can lead to DNA compaction and a repressive chromatin state. HDAC1, 2 and 6 were found to be highly expressed in DLCBL and peripheral T-cell lymphoma (PTCL) [30] and a prognostic significance was ascribed to HDAC2 in cutaneous T-cell lymphoma (CTCL) [31]. Furthermore, HDACs are frequently found in complexes with oncogenic fusion proteins, such as TEL–AML1 in childhood acute lymphoblastic leukemia or PLM–RAR in acute promyelocytic leukemia, causing repression of target genes (Figure 2)[16,32]. Similarly, the oncoprotein BCL6, which is frequently affected in NHL, recruits corepressor complexes, including HDACs, to repress differentiation programs in lymphoma cells [33]. Recent evidence demonstrated that the oncogene MYC recruits HDAC3 to specifically repress a set of miRNAs in various NHLs, providing novel mechanistic insight into MYC-driven lymphomagenesis [34,35]. Furthermore, HDAC3 was mechanistically implicated in STAT3-positive DLBCL, as a direct interaction partner of STAT3, important for STAT3 phosphorylation and activity [36].

Recent attention regarding chromatin-modifying enzymes has also been paid to the polycomb group (PcG) protein EZH2, which is part of the polycomb repressive complex, PRC2, and is responsible for trimethylation of histone H3 Lys27 (H3K27me3) [37]. EZH2 is normally downregulated in naive and late GCB, but upregulated in actively proliferating GCB [38,39]. In DLBCL, it was demonstrated that EZH2 is important for G2/S transition and represses cell cycle-related tumor suppressor genes via trimethylation of H3K27 [38], thus, contributing to disease progression. Interestingly, the protein was found to be mutated in 7% of FL, 22% of GCB DLBCL [40], 7% of BL [41] and in myeloid malignancies [42]. Furthermore, several other NHL, including proliferating MCL [43], ALCL [44] and adult T-cell leukemia/lymphoma [45], also show strong expression of EZH2. In FL and GCB DLBCL, the most frequent EZH2 point mutations affect Y641 and A677 in the catalytically active SET domain, and gain-of-function mutations have also been detected for A687 [40,46,47]. Y641 mutants show a decreased affinity for un- and mono-methylated H3K27 substrates, and an increased activity on dimethylated peptides. As the presence of wild-type EZH2 is needed for mono- and di-methylation, H3K27me3 levels are only increased in lymphoma cells harboring heterozygous EZH2 mutations [48], whereas the A677 mutation shows similar affinity for all H3K27 methylation states [47]. H3K27me3 marks are removed by the histone demethylase UTX, which belongs to the Jumonji family of transcription and chromatin regulators [49–51]. Although EZH2 mutations seem to be common events in DLBCL and FL, no mutations have been described for the UTX gene (except in the DLBCL cell line HT) [40,52], whereas UTX mutations were described in acute myeloid leukemia, chronic myelogenous leukemia, T-cell acute lymphoblastic leukemia, multiple myeloma, Hodgkin’s lymphoma and several other cancer types [53]. Similarly, no mutations in other components of the PRC2 complex, such as SUZ12 and EED, have been found in these studies, indicating that EZH2 gain-of-function mutations favoring increased H3K27me3 levels are specific for DLBCL and FL. In addition, loss-of-function mutations were observed for the H3K4 trimethylase MLL2 in 89% of FLs and 32% of DLBCLs [54–56]. In these cases, the catalytically active SET domain of MLL2 was disrupted by truncation and frameshift mutations, thus, likely inactivating the protein and reducing H3K4 methylation levels. This is especially remarkable as MLL/trithorax histone methyltransferases (HMTs; e.g., MLL2) and PcG proteins (e.g., EZH2) have opposing functions; whereas H3K27 trimethylation by EZH2 is associated with gene repression, methylation of H3K4 is linked to gene expression [57]. As MLL2 forms a complex with the H3K27 demethylase UTX [49,58], activating H3K4 methylation is also linked to demethylation of repressive H3K27me3.

Moreover, mutations leading to a disturbed balance in chromatin modifications have been detected in genes coding for the histone acetyltransferases (HATs) CREBBP and EP300 [59], and HAT-recruiting protein MEF2B [56,60]. Deletions and/or somatic mutations in the HAT-coding domain of CREBBP or EP300 were seen in approximately 39% of DLBCL and 41% of FL cases [60], and 13% of GCB DLBCL and 15% of FL displayed recurrent point mutations in the MADS box or MEF2 domains of the MEF2B gene [54]. HAT lesions commonly affected only one allele, suggesting that reduced HAT activity is important for lymphomagenesis. Regarding MEF2B, no mutations were detected in activated B-cell cases of DLBCL or other NHLs, indicating that MEF2B mutations are specific for GCB DLBCL and FL [54]. Acetylation of H3K27 can be catalyzed by CREBBP/EP300 and EZH2 activity is able to prevent binding of these acetyltransferases to PcG target genes [61], thus, either loss-of-function (HATs) or gain-of-function (HMTs) mutations in these enzymes can result in reduced acetylation and enhanced methylation in FL and DLBCL (Figure 2). Furthermore, overexpression of other chromatin remodelers, such as the PCR complex proteins SUZ12 or BMI1, together with EZH2, has been described in MCL and in B-cell NHL [62,63], and mutations in SWI/SNF chromatin remodelers ARID1A and SMARCA4 have been detected in BL in a mutually exclusive manner [41]. Thus, a disturbed balance between active and repressive chromatin marks with a shift towards the repressed state and mutations in epigenetic enzymes seems to be connected with malignant processes in NHL (Figure 2). In future studies, it will be of particular interest to elucidate which biological processes are predominantly affected by the observed mutations during lymphomagenesis.

Cancer-specific epigenetic modifications are not only seen in chromatin protein alterations, but also in changes in DNA methylation patterns. Interestingly, DNA methylation profiling of mature B-cell lymphoma revealed that de novo methylated regions in all B-cell lymphoma subtypes analyzed were significantly enriched for polycomb targets in embryonic stem cells [64]. Aberrant DNA methylation of genes already repressed by PcGs in precursor cells is found in a wide variety of cancer types [65–67]. This epigenetic switch from PcG silencing to DNA methylation silencing, which is found across all B-cell lymphomas, might reflect a stable acquirement of stemness during lymphomagenesis by chromatin remodeling and subsequent locking of this state via DNA methylation [64].

The role of DNA methylation and its relation to chromatin modifications has been more intensely studied in mouse models for hematopoietic and leukemia stem cells, as it has recently been shown in mice that DNMT3A, a de novo DNA methyltransferase (DNMT), silences hematopoietic stem cell self-renewal [68]. Interestingly, inactivating DNMT3A mutations have been detected together with mutations in methylcytosine dioxygenase TET2 in a subset of angioimmunoblastic T-cell lymphoma and PTCL-NOS patients (11%) [69]. In addition, it has been shown in mice that aberrant expression of DNMT3B7, a truncated isoform of DNMT3B, which is found to be overexpressed in human tumors, and a reduction in DNMT3B levels are able to accelerate lymphomagenesis [70,71], whereas, in patients with DLBCL, DNMT3b protein overexpression was correlated with resistance to treatment, and shorter overall and progression-free survival [72].

It was demonstrated in mice with gradually diminished methylation levels that DNMT1 is essential for self-renewal of hematopoietic stem cells [73,74], and experiments in a murine mouse model of acute myeloid leukemia suggest that DNMT1 might influence the proliferation capacity of leukemia stem cells by the repression of bivalent chromatin domains [75].

In summary, various mutations affecting chromatin-regulating enzymes and remodelers, and deregulation/mutation of DNMTs act in a concerted fashion to reprogram the epigenome of lymphoma cells to allow for sustained proliferation and tumor progression (Figure 2). Thus, inhibition of proteins involved in epigenetic processes might be a suitable strategy for selective and specific targeting of NHL cells.

Epigenetic drugs

We will focus on the most important drugs targeting epigenetic enzymes with potential use in NHL, including DNA methylation inhibitors, HDACis, HMT inhibitors and bromodomain (BRD) inhibitors (Tables 2 & 3).

▪ DNA methylation inhibitors

The two most prominent inhibitors of DNMT function are the nucleoside analogs 5-aza-cytidine (5-aza-CR; Vidaza^®, Celgene, NJ, USA) and the more stable deoxy-derivative 5-aza-2´-deoxycytidine (5-aza-CdR; decitabine) (Table 2)[76]. Both 5-aza-CR and 5-aza-CdR are administered parenterally, but derivatives for oral administration, such as zebularine, are in preclinical studies [77]. On the molecular level, the nucleoside analogs are incorporated into DNA (and RNA in the case of 5-aza-CR) of actively proliferating cells, where they form covalent complexes with DNMTs. Thus, they inactivate the enzyme and inhibit propagation of DNA methylation during each round of replication. This effect is predominant at low concentration levels, whereas at high doses, cytotoxic side effects, such as myelosuppression, occur [78–80]. 5-aza-CR also mediates part of its antiproliferative effect via incorporation into RNA, which leads to disassembly of polyribosomes and subsequently inhibits protein synthesis [81]. In vitro treatment of cell lines with DNMT inhibitors can also result in re-expression of methylated tumor suppressor genes, such as CDH13 in DLBCL [82], Lamin A/C in a BL cell line [83], and p16^INK4A and SHP1 in ALK⁺ ALCL [84,85].

Resistance against DNMT inhibitors can develop due to low numbers of nucleoside transporters involved in drug uptake, low levels of (deoxy)cytidine kinase, which phosphorylates the nucleoside analogs and converts them to their active form, and high levels of cytidine deaminase, which catalyzes the inactivation of cytidine and deoxycytidine to uridine and deoxyuridine [86]. The presence of cytidine deaminase in solid organs, such as the liver or spleen, and suboptimal plasma levels (plasma half-life is approximately 20 min) might explain why the treatment of solid tumors with 5-aza-CdR led to only limited responses [87–89]. However, cotreatment with tetrahydrouridine, an inhibitor of cytidine deaminase, could potentially raise oral bioavailability [90]. Dosing schedules and exposure times are important for effective tumor cell eradication, as nucleoside analogs are S-phase specific and, therefore, have to be administered in such a way that all cancer cells enter S-phase during drug exposure [91]. The major side effects observed in patients include myelosuppression, accompanied by severe neutropenia, thrombocytopenia and anemia [80,92].

Currently, 5-aza-CR and 5-aza-CdR have been approved by the US FDA for the treatment of myelodysplastic syndrome [93]. Regarding treatment of NHL, several Phase I studies with 5-aza-CdR have been conducted in lymphoma patients, although with moderate efficacies. In one study, including DLBCL and MCL patients, dose-limiting myelosuppression, but no changes in global methylation or gene re-expression were observed [94], whereas in a Phase I trial, 5-aza-CdR reduced DNA methylation in refractory lymphomas, but response to therapy was moderate [95]. In another Phase I study, including NHL patients, that evaluated the safety and preliminary efficacy of the cotreatment of 5-aza-CdR with the HDACi vorinostat, no objective tumor response was observed (Table 3)[96]. However, as synergistic effects of HDACis and 5-aza-CdR cotreatment can be observed in vitro[97], and 5-aza-CR or 5-aza-CdR could, therefore, sensitize tumor cells towards chemotherapeutic agents, the focus of current and future studies in this area lies in evaluating the synergistic effects of DNMT inhibitors with other drugs.

▪ HDAC inhibitors

General HDACis are able to inhibit the activity of class 1, 2 and 4 HDACs, whereas class 3 HDACs (so-called sirtuins) belong to a NAD-dependent, structurally unrelated subfamily [98]. We will only address inhibitors targeting class 1, 2 and 4 HDACs in this review. HDACis comprise hydroxamic acid derivatives (vorinostat, givinostat, abexinostat, panobinostat, belinostat and trichostatin A), carboxylates (sodium butyrate), benzamides (entinostat and mocetinostat) and cyclic peptides (depsipeptide and trapoxin). Most drugs show some activity against class 1, 2 and 4 HDACs [99], and it has been reported that entinostat shows a preference for class 1 HDACs [100–102], rocilinostat for HDAC6 [103] and mocetinostat for HDAC1, 6 and 8 [104], respectively.

Involvement of HDACs in cancer development was first demonstrated in acute promyelocytic leukemia [98]. In acute promyelocytic leukemia, leukemic cells arrest at a promyelocytic stage of myeloid differentiation due to the fusion proteins PML–RAR or PLZF–RAR, which are found in HDAC-containing complexes and repress genes required for differentiation [98,105]. Physiological doses of the regulatory molecule retinoic acid (RA) are not able to induce differentiation when these fusion proteins are present, but treatment with higher doses of RA leads to dissociation of the HDAC complexes and subsequent differentiation of PML–RAR cells. For PLZF–RAR, even higher RA doses do not induce dissociation, but combining RA with HDACi in this case is very effective in adding acetylated histone marks and inducing gene transcription [106]. It has been shown in several cell lines including DLBCL, T-cell lymphoma and CTCL cell lines, that HDACis stimulate growth arrest, differentiation or apoptosis in vitro and in vivo[107–109]. Besides influencing chromatin states, HDACis might also exert their effects by other mechanisms, for example, by HDACi-mediated accumulation of DNA damage [110,111]. Given that cell cycle checkpoints, such as the G2-phase and the mitotic spindle checkpoint, are often disrupted and DNA damage stays unrepaired in tumor cells, cells are much more likely to enter apoptosis after chemotherapy and radiotherapy treatments. In some cell lines, HDACis induce growth arrest by upregulation of p21 and cell death via caspase-dependent and -independent pathways [112,113], or lead to promoter hyperacetylation of death receptor pathway genes, including TRAIL, DR5, FAS and FASL, which are required for apoptosis in leukemic cell lines [114,115]. It has become increasingly clear that HDACis alter the function of many nonhistone proteins, as acetylation/deacetylation can influence protein localization, protein–protein interactions and protein stability. Examples are the acetylation of STAT3 (signal transducer and activator of transcription), which triggers cytosolic dimerization and subsequent nuclear translocation [59], or the acetylation of p53, which destabilizes its interaction with Mdm2 and is required for p53 activation [116]. Furthermore, each HDAC might exert distinct functions in different tissues, ranging from involvement in memory formation and synaptic plasticity, as observed for HDAC2 in murine neuronal cells [117], to enhancement of proliferation and malignant transformation in T cells, as observed in T-cell specific deletions of HDAC1 and 2 [118,119]. Therefore, targeting individual HDACs with HDAC-selective HDACis might – depending on the tumor type – provide a way to specifically affect tumor cells, but it has to be taken into account that targeting the ‘wrong’ HDAC could similarly promote tumor formation in otherwise healthy cells. Along this line, a dual role for HDACs has been described in leukemogenesis and lymphomagenesis, where depletion of HDAC1 and 2 can accelerate tumorigenesis, suggesting that HDACs have an oncosuppressive or tumor suppressive role in premalignant stages [118–120].

Class 1 HDACs (HDAC1, 2, 3 and 8) were found to be highly expressed in lymphoid cell lines and tissue sections from primary lymphoid tumors, whereas class 2 HDACs (HDAC4, 5, 6, 7, 9 and 10) showed a more heterogeneous expression pattern [121]. HDAC6 was detected with low frequency, indicating that class 1 HDACs are probably the most important therapeutic targets of HDACis in lymphoid malignancies [121]. Interestingly, the HDAC8-specific inhibitor PCI-34051 was able to selectively induce apoptosis in tumor T-cell-derived cells, including the peripheral T-cell lymphoma cell line HuT78, demonstrating that HDAC8 is of special importance in certain lymphoid malignancies [122]. Although the mechanism of PCI-34051 action is not clear, drug treatment did not lead to detectable histone acetylation, but PCI-34051-induced apoptosis depended on PLC-γ activation and Ca²⁺ in sensitive cell lines.

Regarding pharmacologic parameters of HDACis, several inhibitors, such as vorinostat, mocetinostat and entinostat, can be administered orally, whereas romidepsin is administered intravenously [123–126]. Generally, HDACis have a half-life of approximately 2–8 h in plasma, and undergo hepatic metabolism and intestinal excretion. A prolonged half-life of up to 89 h was observed for entinostat in patients with solid tumors or lymphoma [127]. Common side effects include myelosuppression, fatigue, nausea, vomiting and anemia [128–131].

Recently, the FDA licensed the HDACi vorinostat for the treatment of refractory CTCL (Table 2)[123,132]. CTCL patients treated with vorinostat showed a 30% response rate in two Phase II clinical trials and vorinostat treatment resulted in a higher relief from pruritus compared with other agents [133,134]. The therapeutic action of the drug in CTCL patients might be due to selective induction of apoptosis in malignant T cells, as vorinostat caused an accumulation of acetylated histones, p21^WAF1, BAX, STAT6 and caspase-3 in a panel of CTCL cell lines and induced higher apoptosis rates in peripheral blood mononuclear cells isolated from CTCL patients than from healthy donors [108]. In addition, a Phase II study with vorinostat in patients with relapsed FL, marginal zone lymphoma and MCL revealed efficacy in both FL (47% response rate) and marginal zone lymphoma (22% response rate), but not in MCL (no response) [135]. Oral vorinostat was also tolerated, but had limited activity in a Phase II trial against relapsed DLBCL [136].

Another HDACi that has recently been licensed for treating CTCL and PTCL is the bicyclic peptide depsipeptide (romidepsin) (Table 2). Romidepsin’s CTCL approval was based on two clinical studies with similar objective response rates (34 and 35%) and a complete response rate of 6% [126,137]. Response rates were also observed in patients with relapsed and refractory PTCL (25%) [138] and in subtypes including PTCL-NOS, angioimmunoblastic T-cell lymphoma, ALK^– ALCL and enteropathy-associated T-cell lymphoma (38%) [139].

Furthermore, recent Phase II and III clinical trials with the isotype-selective HDACi mocetinostat in refractory or relapsed FL [124] and the pan-HDACi panobinostat in patients with relapsed CTCL [140] also showed promising results, whereas for entinostat only Phase I studies including lymphoma patients have been published so far [125]. Currently, there is a multitude of ongoing clinical trials involving these and other HDACis in NHL, demonstrating the high antineoplastic potential of these drugs in lymphoma patients (Table 3).

▪ HMT inhibitors

HMT inhibitors are a novel class of epigenetic drugs that might be of special relevance in the treatment of NHL that harbor mutations in HMTs. In particular, inhibition of gain-of-function mutants of EZH2 could be of relevance, as this enzyme has been shown to be mutated in 7% of FL and 22% of DLBCL patients [40]. A recently introduced HMT inhibitor is 3-deazaneplanocin A (DZNep), which was originally described to specifically degrade the PCR2 complex and lead to the reduction of H3K27me3 levels [141]. Mechanistically, DZNep is an inhibitor of S-adenosylhomocysteine hydrolase, an enzyme that catalyzes the conversion of adenosylhomocysteine to adenosine and homocysteine. Adenosylhomocysteine is produced by methyltransferases from the methyl donor S-adenosylmethionine, and accumulation of adenosylhomocysteine inhibits methyltransferases and leads to their degradation. For DZNep, it has been shown that the drug does not only degrade PCR2, but globally inhibits histone methylation and affects both repressive and active histone marks, which results in the reactivation of developmental genes not silenced by DNA methylation [142]. DZNep has been shown to cause cell cycle arrest and apoptosis in human cultured MCL cell lines, and cotreatment with the deacetylase inhibitor panobinostat synergistically enhanced these effects [143]. Examples of other HMT inhibitors in preclinical studies with specificity reported against individual HMTs are the fungal metabolites chaetocin (SU[VAR]3–9) [144] and sinefungin (SETD2) [145], the bacterial polyketide nahuoic acid (SETD8) [146], the quinazoline derivative BIX01294 (G9a) [147] and the small molecule inhibitor adenosine dialdehyde, which shows global HMT inhibition [142].

Two promising new HMT inhibitors, GSK126 and EPZ005687, with high specificity for EZH2 have recently been described [52,148]. Both compounds show high selectivity against the closely related enzyme EZH1 and other human methyltransferases. GSK126 inhibited wild-type and mutant Y641 EZH2 equally well, and induced a 50% loss of H3K27me3 levels in wild-type and mutant DLBCL cell lines, whereas PCR2 components were not affected by the drug [52]. In drug-sensitive cell lines, transcriptional activation of formerly H3K27me3 repressed genes was noted, whereas in drug-insensitive cell lines minimal transcriptional changes occurred. In xenograft studies, treatment of xenografted mice resulted in either tumor regression or complete tumor inhibition, depending on dosing regimens, and GSK126 was well tolerated without significant changes in any blood cell types. Similarly, EPZ005687 was inhibiting wild-type and mutant EZH2 equally well and induced apoptotic cell killing in heterozygous mutant Tyr641 and Ala677 lymphoma cells [148]. Thus, EZH2 inhibition might be an interesting strategy for the treatment of DLBCL, FL and other cancer entities harboring activating EZH2 mutations, but it has to be evaluated in further studies whether the selective EZH2 inhibitor also provides clinical benefit for lymphoma patients.

▪ BRD inhibitors

Many chromatin-remodeling proteins contain a specific protein domain called BRD, which is an evolutionary conserved protein module that recognizes and targets protein complexes to acetylated lysines at histones H3 and H4 [149]. BRD-containing proteins are, for example, the HATs CREBBP and EP300 [150,151], the HMT MLL2 [152], and the SWI/SNF chromatin-remodeling complex member SMARCA4 [153]. Inhibition of BRD-containing proteins could provide a possibility to selectively alter protein interactions that have a direct influence on chromatin organization and gene expression. Recently, the BRD inhibitors JQ1, iBET and the benzodiazepine derivative GW841819X were shown to specifically inhibit BET family members [154–156]. The BET group of proteins includes BRD4, which is involved in the regulation of c-MYC function and, thus, represents a rational target for inhibition of this prominent oncogene [157,158]. The BRD inhibitor JQ1 showed antiproliferative activity in both leukemia and lymphoma cell lines, and was able to successfully suppress c-MYC function by inhibiting BRD4 [158]. BRD4 inhibition resulted in reduced transcription of c-MYC target genes and in reduced tumor load in xenograft models, which suggests that BRD inhibitors that target BRD4 could be of special interest in tumors with deregulated c-MYC expression, such as BL.

Combination therapies

Aside from their efficacy as single treatment regimens, epigenetic drugs might be efficient when used in combination with other epigenetic or standard therapies. Combination therapies of DNMT and HDACis have long been recognized to exert synergistic effects on the re-expression of tumor suppressor genes and apoptosis of tumor cells [159]. Expression of the surface antigen CD20 could be restored in B-cell lymphomas after treatment with 5-aza-CdR [160] and the HDACi SAHA showed synergistic effects with rituximab, a monoclonal antibody directed against CD20, in MCL [161]. Furthermore, HDACis may sensitize tumor cells against standard chemotherapy as observed in DLCBL or BL [162,163]. Thus, epigenetic drugs might be useful to limit resistance against currently used therapies and provide a possibility to lower chemotherapy doses in order to limit toxicities and adverse effects.

Future perspective

Recent advances in next-generation sequencing technologies have produced a multitude of information on genomic and epigenomic alterations in various malignancies [164]. The identification of recurrent mutations in NHL provides a rationale to develop epigenetic therapies, which are already successful in preclinical and clinical trials, and will be important players in selective and personalized therapy in the future. Furthermore, identification of epigenetic alterations and mutations in epigenetic enzymes might provide novel classification options for some currently unclassifiable lymphoma subtypes such as PTCL-NOS. In addition, epigenetic alterations hold great promise as valuable biomarkers, which can be used for lymphoma diagnosis, prognosis and therapy prediction in the future, which will result in major advances in the daily clinical routine.

**Table 1. Non-Hodgkin’s lymphoma classification.**
Name	Putative cell of origin	Recurrent genetic abberration	Involved oncogenes	Relative frequency (%)	Ref.
*B-cell lymphomas*
B lymphoblastic leukemia/lymphoma	Hematopoietic stem cell, B-cell progenitor cell	t(9;22) t(v;11q23) t(12;21) t(1;19)	BCR–ABL MLL TEL–AML1 E2A–PBX1	– – – –	[165–168]
Mantle cell lymphoma	Naive pregerminal center B cell	t(11;14) t(12;14)	CCND1 CCND2	7	[18] [169]
Follicular lymphoma	Germinal center B cell	t(14;18) t(3;v)(q27;v)	BCL2 BCL6	29	[18] [170]
Primary cutaneous follicle center lymphoma	Germinal center B cell	–	C-REL	–	[171]
B-cell prolymphocytic leukemia	Mature B cell	–	–	–	–
CLL/small lymphocytic lymphoma	Naive (unmutated subset) and memory B cell (mutated subset)	Trisomy 12 del(13q)	–	12	[172] [173]
MALT lymphoma	Postgerminal center marginal zone B cell	t(11;18) t(1;14) t(14;18) t(3;14) trisomy 3, 18	API2–MALT1 BCL10 MALT1 FOXP1 –	9	[174] [18] [175] [176] –
Nodal marginal zone lymphoma	Postgerminal center marginal zone B cell	t(14;19) Trisomy 18, 7	BCL3	2	[177]
Splenic B-cell marginal zone lymphoma	Antigen-experienced B cell	del(7q) t(2;7) t(11;14)	CDK6 CCND1	0.9	[178]
Hairy cell leukemia	Late activated memory B cell	t/del(14q)	–	–	[179]
Plasma cell neoplasms	Plasma cell	t(11;14) t(4;14) t(6;14) t(14;16) t(1;14)	CCND1 FGFR3, MMSET IRF4 c-MAF IRTA1/IRTA2	>10	[180]
Lymphoplasmacytic lymphoma	Postfollicular B cell	t(9;14) del(6q) –	PAX5 – MYD88^†	1.40	[18] [181] [182]
DLBCL-NOS	Germinal center or postgerminal center B cell	t(3;14) t(14;18) t(8;14) –	BCL6 BCL2 MYC MYD88^†	37	[18] [18] [18] [183]
T-cell/histiocyte-rich large B-cell lymphoma	Germinal center B cell	Gain of Xq, 4q13q28, Xp21p11, 18q21, loss of 17p	–	–	[184]
Primary DLBCL of the CNS	Activated B cell	t(3;14)	BCL6	–	[18]
Primary cutaneous DLBCL, leg type	Postgerminal center B cell	t(8;14) del(9p21.3)	MYC CDKN2A, CDKN2B	– –	[185]
EBV+ DLBCL of the elderly	Mature B-lymphocyte, transformed by EBV	–	–	–	–
DLBCL associated with chronic inflammation	Mature B lymphocyte, transformed by EBV	–	–	–	–
Lymphomatoid granulomatosis	Mature B lymphocyte, transformed by EBV	–	–	–	–
Primary mediastinal (thymic) large B-cell lymphoma	Thymic medullary B cell	Gains in 9q24 Gains in 2p15	REL, PDL1, PDL2 BCL11A	3	[186]
Intravascular large B-cell lymphoma	Transformed peripheral B cell	–	–	–	–
ALK⁺ large B-cell lymphoma	Postgerminal center B cell with plasma cell differentiation	t(2;17)	ALK–CLTC	–	[187]
Primary effusion lymphoma	Postgerminal center B cell	–	–	–	–
Plasmablastic lymphoma	Plasmablast	–	–	–	–
Burkitt’s lymphoma	Germinal center B cell	t(8;14) t(8;22) t(2;8) – –	MYC MYC MYC TCF3^† ID3^†	0.8 0.8 0.8 – –	[17] [17] [17] [188] [188]
*T-cell lymphomas*
T-lymphoblastic leukemia/lymphoma	T-cell progenitor, thymic lymphocyte	t(7;10), t(10;14), t(5;14)	HOX11, HOX11L2	–	[189]
T-cell prolymphocytic leukemia	–	inv(14), t(14;14) t(X;14)	TCL1A MTCP1	– –	[190] [191]
T-cell large granular lymphocytic leukemia	CD8⁺ T cell	–	–	–	–
Chronic lymphoproliferative disorders of NKs	NK	–	–	–	[3]
Aggressive NK leukemia	NK	del(6)(q21q25)	–	–	[192]
Adult T-cell leukemia/lymphoma	CD4⁺ T cell	t/der(14q32) t/der(14q11) del(6q)	BCL11B	9.6	[193] [194] –
Extranodal NK/T-cell lymphoma, nasal type	Activated NK	del(6)(q21q25) i(6)(p10)	–	10.4	[195]
Enteropathy associated T-cell lymphoma	Intraepithelial T cell of the intestine	Gains of 9q31.3-qter del(16)(q12.1)	– –	4.7	[196]
Hepatosplenic T-cell lymphoma	Peripheral γδ cytotoxic memory T cell	i(7q)(q10) Trisomy 8	– –	1.4	[197]
Peripheral T-cell lymphoma-NOS	Activated mature T lymphocyte	t(14;19) t(5;9)	PVRL2 ITK–SYK	25.9	[198] [6]
Angioimmunoblastic T-cell lymphoma	CD4⁺ follicular helper T cell	Trisomy 3 Trisomy 5 + X	– – –	18.5	[199]
Anaplastic large-cell lymphoma, ALK⁺	Activated mature cytotoxic T cell	t(2;5) Variant translocations involving ALK	NPM–ALK	6.6	[200]
Anaplastic large-cell lymphoma, ALK^–	Activated mature cytotoxic T cell	–	–	5.5	–
Subcutaneous panniculitis-like T-cell lymphoma	Mature cytotoxic αβ T cell	–	–	0.9	–
Mycosis fungoides	Mature skin homing CD4⁺ T cell	Monosomy 10 Monosomy 9 Trisomy 18	– – –	– – –	[201]
Primary cutaneous CD30⁺ T-cell lymphoproliferative disorders	Activated skin homing T lymphocytes	–	–	–	–

List of various non-Hodgkin’s lymphomas based on cellular origin, genetic translocation, involved oncogenes or mutations in specific genes and incidence rates.

^†Mutation in a specific gene.

CLL: Chronic lymphocytic leukemia; DLBCL: Diffuse large B-cell lymphoma; EBV: Epstein–Barr virus; MALT: Mucosa-associated lymphoid tissue; NK: Natural killer cell; NOS: Not otherwise specified.

**Table 2. Epigenetic drugs approved by the US FDA.**
Name	Chemical structure	Target	Approval (year)	Trade name (company)	Application	Adverse effects
*DNMT inhibitors*
5-aza-cytidine	Nucleoside analog	DNMT1	MDS (2004)	Vidaza^® (Celgene, NJ, USA)	iv., sc.	Myelosuppression
5-aza-deoxycytidine	Nucleoside analog	DNMT1	MDS (2006)	Dacogen^® (Eisai, Tokyo, Japan; and Johnson & Johnson, NJ, USA)	iv., sc.	Myelosuppression
*HDAC inhibitors*
Vorinostat	Hydroxamic acid	HDACs	CTCL (2006)	Zolinza^® (Merck, NJ, USA)	p.o.	Diarrhea, fatigue, nausea, anorexia
Romidepsin	Cyclic peptide	HDACs	CTCL (2009), PTCL (2011)	Istodax^® (Celgene)	iv.	Nausea, fatigue, infections, anemia

List of currently approved epigenetic drugs.

CTCL: Cutaneous T-cell lymphoma; DNMT: DNA methyltransferase; iv.: Intravenous; HDAC: Histone deacetylase; MDS: Myelodysplastic syndrome; p.o.: Per orem; PTCL: Peripheral T-cell lymphoma; sc.: Subcutaneous.

**Table 3. Selected examples of epigenetic drugs in preclinical settings and highest completed clinical studies in non-Hodgkin’s lymphoma.**
*Name*	*Chemical structure*	*Target*	*Completed clinical studies (NHL)*	*Clinicaltrials.gov identifier*
*DNMT inhibitors*
5-aza-cytidine	Nucleoside analog	DNMT1	Phase II	NCT00005639
5-aza-deoxycytidine	Nucleoside analog	DNMT1	Phase II	NCT00882206
*HDAC inhibitors*
Vorinostat	Hydroxamic acid	HDACs	Approved (CTCL); Phase II	–
Romidepsin	Cyclic peptide	HDACs	Approved (CTCL)	–
Panobinostat	Hydroxamic acid	HDACs	Phase II/III (CTCL)	NCT00490776
Belinostat	Hydroxamic acid	HDACs	Phase II	NCT00274651
Mocetinostat	Benzamide	HDAC1, 6, 8	Phase II	NCT00543582
Entinostat	Benzamide	HDAC1, 2, 3, 8	Phase I	NCT00098891
Abexinostat	Hydroxamic acid	HDACs	Phase I	NCT00562224
Quisinostat	Hydroxamic acid	HDACs	Phase I	NCT00677105
Rocilinostat	Hydroxamic acid	HDAC6	–	–
*HMT inhibitors*
3-deazaneplanocin A (DZNep)	Nucleoside	HMTs, PRC2	Preclinical	–
GSK126	Carboxamide	EZH2	–	–
EPZ005687	Carboxamide	EZH2	–	–
Sinefungin	Nucleoside derivative	SETD2	–	–
Nahuoic acid	Polyketide	SETD8	–	–
Adenosine dialdehyde	Nucleobase	HMTs	–	–
BIX01294	Quinazoline	G9a	–	–
Chaetocin	Diketopiperazine	SU(VAR)3–9	–	–
*BRD inhibitors*
JQ1	Diazepine	BET proteins	Preclinical	–
iBET	Diazepine	BET proteins	–	–
GW841819X	Diazepine	BET proteins	–	–

Compendium of epigenetic drugs currently under preclinical and clinical evaluation. Details of each trial can be found on www.clinicaltrials.gov and by searching for the relevant trial number.

BRD: Bromodomain; CTCL: Cutaneous T-cell lymphoma; DNMT: DNA methyltransferase; HDAC: Histone deacetylase; HMT: Histone methyltransferase; NHL: Non-Hodgkin’s lymphoma.

Executive summary

Classification of non-Hodgkin’s lymphoma based on clinical & molecular parameters

▪ Non-Hodgkin’s lymphomas (NHLs) are classified according to cell of origin and differentiation stage.
▪ Recurring oncogenic translocations are characteristic for certain NHL subtypes.

Disruption of chromatin biology in NHL

▪ Epigenetic changes in NHL arise from deregulation of chromatin-modifying enzymes and DNA methyltransferases (DNMTs). Frequently observed events comprise activating mutations in the histone methyltransferase EZH2 and inactivating mutations in the histone methyltransferase MLL2 and the histone acetyltransferases CREBBP and EP300.
▪ A common feature of cancer cells observed in certain NHL types is an epigenetic switch from flexible polycomb group silencing to permanent DNA methylation silencing of specific genomic regions.

Epigenetic drugs

▪ Epigenetic drugs target both histone modifications and DNA methylation in cancer cells by inhibiting specific epigenetic enzymes.

DNA methylation inhibitors

▪ The nucleoside analogs 5-aza-cytidine (Vidaza^®; Celgene, NJ, USA) and 5-aza-2´-deoxycytidine (decitabine) trap DNMTs at the DNA and inhibit propagation of DNA methylation during S-phase.
▪ Clinical studies with the drugs have shown low-to-moderate response rates in NHL patients. However, the combination of DNMT inhibitors with other drugs might result in synergistic antineoplastic effects.

Histone deacteylase inhibitors

▪ HDACis target HDACs and induce differentiation, apoptosis or cell cycle arrest. HDACis for individual HDAC classes have been developed and the HDACis vorinostat and romidepsin have been US FDA approved for the treatment of cutaneous T-cell lymphoma and peripheral T-cell lymphoma.
▪ HDACis are the most extensively tested and currently most successful epigenetic drugs in clinical studies of NHL.

Histone methyltransferase inhibitors

▪ Histone methyltransferase selective inhibitors aim to change particular aberrant epigenetic enzymes in cancer cells.
▪ Promising preclinical data for selective targeting in NHL have been obtained for the EZH2-specific inhibitors GSK126 and EPZ005687.

Bromodomain inhibitors

▪ Bromodomains are frequently found in chromatin-remodeling proteins and allow for specific binding of proteins to acetylated lysine residues.
▪ BET bromodomain inhibition efficiently targets Myc-dependent lymphomas via inhibition of BRD4.

Combination therapies

▪ Epigenetic drugs can sensitize tumor cells to chemotherapy.
▪ Epigenetic drugs show synergistic effects among themselves or with other standard therapies.

Financial & competing interests disclosure

G Egger was supported by grants from the Austrian Science Fund (FWF), Elise Richter (V102-B12), the Oesterreichische Nationalbank (Anniversary Fund, project number 13061) and the EU-FP7 (Marie Curie International Reintegration Grant 230984). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

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Vol. 5, No. 4

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Published online 29 July 2013

Published in print August 2013

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