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Current Opinion in Hematology:
doi: 10.1097/MOH.0000000000000051
LYMPHOID BIOLOGY AND DISEASES: Edited by Ari M. Melnick

The origin and targeting of mucosa-associated lymphoid tissue lymphomas

Martinez-Climent, Jose A.

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Division of Hematological Oncology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain

Correspondence to Jose A. Martinez-Climent, MD, PhD, Division of Hematological Oncology, Center for Applied Medical Research (CIMA) Building, 1° Floor Lab 108, University of Navarra, Avda Pio XII, 55, Pamplona 31008, Spain. Tel: +34 948 194700x1029; fax: +34 948 194714; e-mail: jamcliment@unav.es

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Abstract

Purpose of review: Extranodal mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct clinical–pathological entity that can be distinguished from other lymphomas by a number of unique features, including their location in various extranodal sites, being preceded by chronic inflammatory or infection processes; a characteristic histopathological picture; and the presence of exclusive chromosomal translocations which increase MALT1 proteolytic activity to promote constitutive NF-κB signaling and eventually drive lymphomagenesis.

Recent findings: This review explores the major molecular and cellular events that participate in MALT lymphoma pathogenesis, focusing on gastric MALT lymphoma as a model of chronic inflammation-induced tumor development. In addition, the pivotal roles of activated MALT1 protease, its substrate TNFAIP3/A20, and the MyD88 adaptor protein in abnormally triggering downstream NF-κB pathway are overviewed. These new insights provide a mechanistic basis for using novel therapies targeting MALT1 protease or IRAK4 kinase activities. Finally, the putative cellular origin of MALT lymphomas is also discussed.

Summary: Over the last decade, unraveling the biological complexity of MALT lymphomas has shed light on the fundamental cellular and molecular aspects of the disease that are to be translated into clinical diagnostics and therapy.

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INTRODUCTION

Extranodal marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) can be distinguished from other lymphomas by a number of unique features, such as their varied extranodal location including the stomach (60–70% of the cases), lung (15%), ocular adnexa (10%) and other less frequent sites (thyroid, salivary glands, intestine, skin, and liver), being preceded by chronic inflammatory or infection processes [1–4]; a characteristic histopathological picture with typical lymphoepithelial lesions [1,2]; and the presence of exclusive chromosomal translocations which deregulate MALT1 protease to promote constitutive NF-κB signaling [1,2,5].

This review article summarizes the major molecular and cellular events that contribute to MALT lymphoma development, also providing an overview of the emerging targeted therapeutic strategies with potential use in the clinic. Finally, the putative cellular origins of MALT lymphomas will be discussed.

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CHRONIC INFLAMMATION AND MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA

MALT lymphomas arise in the extranodal organs that are almost usually devoid of lymphoid tissue but that accumulate B lymphocytes in response to persistent inflammation due to chronic infections or autoimmune disorders [4,6]. The best characterized example is gastric MALT lymphoma and Helicobacter pylori infection [7,8]. Other infections correlated with MALT lymphoma include Chlamydia psittaci (ocular adnexa), Borrelia bugdorferi (skin) lymphoma, and Campylobacter jejuni (intestinal) [1–4]. In addition, autoimmune disorders including Sjögren's disease and Hashimoto's thyroiditis predispose to MALT lymphoma development [1–4]. Why only a minority of individuals with chronic infection or autoimmune disorders develop MALT lymphoma is currently unknown, but may be at least partially explained by the presence of predisposing germline variations of MALT1 or TNFAIP3/A20 genes [9,10▪▪].

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H. pylori infection drives a multistep process that transforms a polyclonal B-cell population into a monoclonal B-cell lymphoma (Fig. 1). H. pylori can be subclassified into ‘cag’ pathogenicity island (cagPAI)-positive and cagPAI-negative strains based on the presence of cagPAI, a genome fragment encoding CagA antigenic protein, which is secreted on gastric epithelial surfaces and induces local inflammatory responses to attract B and T lymphocytes [11]. Then, H. pylori-specific activated tumor-infiltrating T cells provide growth signals to B cells through CD40 and CD80/CD86 receptors [12]. H. pylori also recruits CD4+CD25+FOXP3+ regulatory T cells, which impair antitumor T-cell responses [13,14▪]. In addition, CagA-positive H. pylori promotes neutrophil activation and reactive oxygen species (ROS) release [11]. Clonal B-cell expansion is also triggered by continuous antigenic stimulation of the B-cell receptor (BCR), which induces NF-κB signaling [12,15]. Hence, the reactivity of BCRs is restricted not only to H. pylori antigens, but also to multiple other antigens including rheumatoid factors, suggesting their activation by antigen–antibody complexes generated by a polyclonal B-cell response to bacteria [16,17]. H. pylori also translocates secreted CagA into B cells, directly inducing a cascade of events, including activation of SHP-2 tyrosine phosphatase, which in turn induces extracellular signal-regulated kinase and mitogen-activated protein kinase signaling [18–20], and interaction with ASPP2 protein, which enhances the degradation of p53 [11,21].

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Therefore, H. pylori infection orchestrates a myriad of extracellular and intracellular signals to form clonal gastric MALT lymphoma, which at this stage can be eradicated with antibiotics [22,23]. Thereafter, acquisition of MALT1 chromosomal translocations constitutively activating NF-κB provides antigenic independence and antibiotic resistance [2,5,6]. The generation of such chromosomal rearrangements may be the consequence of the DNA damage produced during inflammation, either by CagA-positive H. pylori ROS release [11] or by the inherent genetic instability during somatic hypermutation [24]. Moreover, p53 inactivation as a consequence of CagA–ASPP2 interaction [18] or following overexpression of activation-induced cytidine deaminase induced by CagA [25] may also generate DNA breaks and favor chromosomal translocations [26,27].

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CHROMOSOMAL TRANSLOCATIONS OF MALT1: HALLMARKS OF MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA

The most common translocation is t(11;18)(q21;q21), which generates an API2–MALT1 fusion in 25–30% of the cases [28]. The t(14;18)(q32;q21) translocation is observed in 10–15% of MALT lymphomas, and fuses MALT1 gene and the IGH enhancer, resulting in MALT1 deregulated expression [29,30]. MALT1 is a protease with a conserved dead domain, two immunoglobulin-like domains, and a paracaspase domain that cleaves substrates following arginine or lysine instead of aspartate, like conventional caspases [31–33]. In resting lymphocytes, MALT1 is present in its catalytically inactive form, constitutively associated with the adaptor protein BCL10 [32,33]. In B cells, MALT1 transduces signals from several surface receptors [31,34–38]. Upon BCR engagement, a cascade of tyrosine kinase phosphorylation activates PLC-γ2, which in turn promotes PKC-β activation [31]. PKC-β then phosphorylates the scaffold protein CARD11, promoting a conformational change that enables its interaction with BCL10 and MALT1, leading to the formation of a lipid raft-associated helical filamentous structure termed ‘signalosome’ [39,40,41▪▪]. Once the signalosome is assembled, MALT1 promotes NF-κB activation, by both its scaffold and its enzymatic function [31]. As a scaffold, MALT1 recruits the ubiquitin ligase TRAF6 and the subsequent ubiquitination-dependent recruitment and activation of the IκB kinase (IKK) complex, which phosphorylates and initiates the degradation of the NF-κB inhibitor IκBα [42–44]. As an enzyme with protease activity, MALT1 also promotes NF-κB activation by cleaving the inhibitor RelB, which is subsequently degraded by the proteasome [45]. In addition, MALT1 promotes lymphocyte activation by cleaving TNFAIP3/A20 and CYLD, deubiquitinating enzymes that inhibit NF-κB and the c-Jun N-terminal kinase pathway, respectively [46,47], and by cleavage of BCL10, which promotes lymphocyte adhesion [48], and of Regnase-1, a regulator of T-cell immune activation [49▪▪]. Recent data indicate that monoubiquitination of MALT1 on Lys644 is essential for its catalytic activation [50▪▪]. Overall, MALT1 is an adaptor molecule in antigen receptor signaling to NF-κB, playing a crucial role in regulating lymphocyte survival and proliferation [31].

Gastric MALT lymphomas with t(11;18)(q21;q21) frequently show infection by CagA-positive H. pylori, are resistant to antibiotic therapy, and show increased rates of dissemination and transformation to diffuse large B-cell lymphoma (DLBCL) [51–54,55▪]. The API2–MALT1 protein utilizes multiple mechanisms to activate NF-κB. First, API2–MALT1 triggers canonical NF-κB by constitutive auto-oligomerization via the baculovirusIAP repeat 1 domain of API2, causing deregulated ubiquitin ligase activity of MALT1 and targeting IKKγ for polyubiquitination [56]. Second, API2–MALT1 loses the physiological ubiquitin ligase activity of wildtype API2 on BCL10, consequently stabilizing BCL10 and activating canonical NF-κB [57]. Third, API2–MALT1 recruits TRAF2 to promote RIP1 ubiquitination, which is necessary for canonical NF-κB activation [58▪]. Fourth, API2–MALT1 binds and proteolytically cleaves NF-κB-inducing kinase (NIK), creating a constitutively active NIK fragment that stimulates IKKα and the noncanonical NF-κB pathway [59] (Fig. 2).

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The t(14;18)(q32;q21) translocation occurs more commonly in nongastrointestinal MALT lymphomas and is frequently accompanied by additional genetic aberrations [29,30,60,61]. This translocation, however, has not been associated with infections or inflammatory disorders, and its clinical significance remains unclear. Mechanistically, MALT1 protein overexpression observed in t(14;18)-positive MALT lymphomas may be considered analogous to the MALT1 activation observed in activated B-cell DLBCL (ABC-DLBCL) as a consequence of MALT1 oligomerization mediated by BCL10, which leads to constitutive MALT1 proteolytic activity that cleaves various substrates and promotes NF-κB signaling [33,45,62,63]. This observation, however, awaits experimental demonstration in MALT lymphoma.

A rare but recurrent reciprocal translocation in MALT lymphomas is t(1;14)(p22;q32), which fuses BCL10 to the IGH enhancer, resulting in deregulated expression of BCL10 [64,65]. BCL10 is an apoptosis modulator that connects B-cell and T-cell antigen receptor signaling to NF-κB activation [66]. How BCL10 participates in the lymphomagenesis process remains unknown.

Additional rare translocations in MALT lymphomas are t(3;14)(p13;q32) involving FOXP1, which seems to induce lymphomagenesis without interfering with NF-κB signaling [67–69]. Other recurrent genetic abnormalities including the t(X;14)(p11.4;q32) translocation involving GPR34 have been occasionally reported [70–73,74▪].

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GENE MUTATIONS CAUSING NF-κB ONCOGENIC SIGNALING

Translocations of MALT1 are detected in up to 50% of MALT lymphomas [2,5,60]. However, gene-expression profiling of MALT lymphoma biopsies found a NF-κB transcriptional signature common to virtually all cases irrespective of chromosomal translocations, suggesting that other genetic abnormalities are responsible for abnormal NF-κB signaling [75▪,76,77]. Accordingly, bi-allelic inactivation of the NF-κB inhibitor TNFAIP3/A20 is detected in 20–25% of MALT lymphomas [10▪▪,78–83]. TNFAIP3/A20 inactivation is caused by homozygous deletion or by hemizygous loss combined with gene mutation (most frequently, frame-shift or nonsense mutations), which are distributed along the entire coding region and produce truncated proteins [10▪▪,78–83]. Loss-of-function mutations of TNFAIP3/A20 induce upregulation of NF-κB pathway activity and resistance to apoptosis [78,84,85]. Importantly, TNFAIP3/A20 is cleaved and inactivated by active MALT1 protease in lymphocytes and in lymphoma cells [46]. Because TNFAIP3/A20 abnormalities are found in MALT lymphomas without MALT1 chromosomal translocations, this may suggest that TNFAIP3/A20 genetic inactivation defines a distinct subgroup of the disease. Accordingly, TNFAIP3/A20 inactivation may associate with adverse clinical parameters and shorter survival of patients with MALT lymphoma [80,81]. Finally, genome-wide association studies have demonstrated a relationship between TNFAIP3/A20 polymorphisms and risk for Sjögren syndrome and other autoimmune disorders, which predispose to MALT lymphoma development [10▪▪]. Functional and mechanistic analyses of the TNFAIP3/A20 and NF-κB interplay will provide further insight into MALT lymphoma pathogenesis (Table 1).

Table 1
Table 1
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Mutations in the MyD88 adaptor protein are found in 6–9% of MALT lymphomas [82,86,87▪,88▪]. Like in ABC-DLBCL, MyD88 missense mutations are clustered in the Toll/IL-1 receptor (TIR) domain, L265P being the most common. MyD88 gain-of-function mutations promote cell survival by activating interleukin-1 receptor-associated kinase 4 (IRAK4) kinase activity, leading to NF-κB signaling by interacting with the IKKγ/β/α complex and to JAK kinase activation of STAT3 [86]. Intriguingly, MyD88 L265P mutation induced NF-κB-mediated B-cell proliferation that was dependent on continuous upstream Toll-like receptor activation and was rapidly countered by the induction of TNFAIP3/A20 expression [89▪▪]. These data may explain why MyD88 L265P mutation accompanies TNFAIP3/A20 genetic inactivation in 25% of ABC-DLBCLs [86]. However, this association has not been evaluated in MALT lymphomas. Detailed high-throughput sequencing studies will define the entire mutation portrait of NF-κB-related genes, and probably in other oncogenic cascades, in MALT lymphomas.

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MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA AND ACTIVATED B-CELL DIFFUSE LARGE B-CELL LYMPHOMA ARE CLOSELY RELATED ENTITIES

Most gastric and nongastric DLBCLs evolved from MALT lymphomas are classified as ABC-DLBCL, suggesting a close relationship between these two lymphoma subtypes [6,55▪,90]. Similarly to MALT lymphomas, ABC-DLBCLs show constitutive NF-κB signaling and are dependent on MALT1 expression for survival [45,62,63,91,92]. However, MALT1 chromosomal translocations are not detected in ABC-DLBCL, but instead genomic amplification of 18q21 chromosome inducing MALT1 gene overexpression is observed in a subset of cases [29,93]. In addition, somatic mutations in gene components of the BCR pathway located upstream of MALT1, including CARD11, CD79A, and CD79B, are found in 35–40% of ABC-DLBCLs [94–96]. Like in MALT lymphomas, genetic inactivation of TNFAIP3/A20 and activating mutations of MyD88 are detected in 30 and 35% of ABC-DLBCLs, respectively [78,86]. The chromosomal translocation t(3;14)(p13;q32) inducing deregulated expression of FOXP1 is also observed in MALT lymphoma and ABC-DLBCL, but not in other lymphoma subtypes [67–69]. Further supporting the strong similarities between MALT lymphoma and ABC-DLBCL, transgenic mice with ectopic expression of MALT1 developed human-like MALT lymphomas that showed aggressive transformation to ABC-DLBCL [75▪]. Therefore, MALT lymphoma and ABC-DLBCL are closely related entities, whereby MALT1 plays a central pathogenetic role and represents an attractive therapeutic target.

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THERAPEUTIC TARGETING OF MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA

The first-line treatment of H. pylori-positive gastric MALT lymphoma with antibiotics results in long-lasting complete remission in up to 80% of patients, without requiring additional treatment [23,97,98,99▪]. Likewise, most patients with ocular adnexa MALT lymphomas respond to doxycycline treatment, especially C. psittaci-positive cases [100,101▪]. Antibacterial treatment, however, remains experimental for all other MALT lymphomas [4,102]. Patients with histologically persisting t(11;18)-positive gastric lymphoma after antibiotics usually receive radiation therapy in stages I and II, or systemic therapy (with chemotherapy and/or rituximab) in disseminated cases [103,104,105▪,106▪]. Treatment of nongastric MALT lymphomas is much less well established, and either radiotherapy or systemic therapy can be effective [107,108]. Overall, up to 75–85% of patients with MALT lymphoma achieve long-term event-free survival [103,104,105▪,106▪,107,108,109▪]. However, patients with refractory or relapsed disease require novel therapies. Thus, lenalidomide [110▪], rituximab with either cladribine [111▪], fludarabine [112▪], bendamustine [113▪], or chlorambucil [114▪], and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitors [115▪,116▪] have been recently evaluated in clinical trials, showing promising results for the majority of patients. Further studies should define optimal therapeutic regimens for patients with refractory, relapsed, transformed or disseminated MALT lymphoma.

The unique molecular pathogenesis of MALT lymphomas can serve to design rational targeted therapies. Although in lymphomas with API2–MALT1 protein blocking NIK kinase activity would theoretically be a valid strategy, blocking constitutive MALT1 proteolytic activity seems a therapeutic approach applicable to both t(11;18)(q21;q21) and t(14;18)(q21;q32)-positive MALT lymphomas. Recently, two groups have found inhibitors of MALT1 activity [117▪▪,118▪▪]. Fontan et al.[117▪▪] discovered a small molecule termed MI-2 that inhibited MALT1 by forming an irreversible covalent linkage in the active site. Nagel et al. found that the antipsychotic drugs phenothiazines inhibited MALT1 proteolytic activity though reversible binding in a pocket located opposite to the paracaspase active site [118▪▪,119]. Both MI-2 and phenothiazines were selectively toxic to ABC-DLBCL cells in vitro and in vivo at low micromolar concentrations. Importantly, as predicted by the previous studies [32,36], mice treated with MI-2 did not have detectable signs of toxicity [117▪▪]. Although it can be assumed that these compounds will be effective in MALT lymphomas, the lack of experimental human cell line models of this lymphoma subtype has precluded preclinical testing.

A different therapeutic target is IRAK4, which becomes activated by the MyD88 L265P mutation, leading to NF-κB signaling [86]. IRAK4 inhibitor molecules have been developed as anti-inflammatory therapeutic agents [120] and are selectively toxic in MyD88-mutated ABC-DLBCL cells [86], suggesting their potential efficacy in patients with MALT lymphomas carrying MyD88 mutations.

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CELL OF ORIGIN OF MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA

Detailed characterization of the molecular structure of the MALT1–IGH fusion revealed the involvement of the V(D)J recombination signal sequences at the IGH locus side of the translocation, indicating its development at the pro-B/pre-B cell stage [29,121]. By contrast, the API2–MALT1 translocation has none of these features and thus likely occurs either at the lymphoid progenitor stage or in mature B lymphocytes [121]. However, targeting MALT lymphoma chromosomal translocations to mouse B cells has failed to reproduce human disease [122–124]. Although most investigators assume that mature B-cell malignancies derive from B lymphocytes, the aforementioned results indicate that these cells may not originate MALT lymphoma, suggesting that these may derive from immature hematopoietic cell populations. In support of this concept, a landmark study revealed that in B-cell chronic lymphocytic leukemia, the propensity to generate clonal B cells is already acquired at the hematopoietic stem cell stage, opening the possibility that similar cell populations may be the source of other B-cell lymphomas [125]. In addition, some patients with B-cell lymphomas harbored inactivating mutations of TET2 gene that occurred in hematopoietic stem cells and promoted lymphoma development [126]. To test this hypothesis, mice with ectopic expression of MALT1 in Sca1+ hematopoietic stem/progenitor cells were generated [75▪]. From 2 months of age, mouse hematopoietic stem/progenitor cells showed abnormal NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation, accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the main clinical, histopathological, genetic, and molecular characteristics of human MALT lymphomas [75▪]. Further paralleling the natural history of human disease, spontaneous transformation of mouse MALT lymphoma to ABC-DLBCL was observed in a fraction of mice and this was accelerated after the constitutive deletion of p53 gene (Fig. 3). This study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, suggesting their putative involvement in the pathogenesis of MALT lymphomas [127].

Figure 3
Figure 3
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CONCLUSION

Over the last decade, unraveling the biological complexity of MALT lymphomas, which can be considered as a model of chronic inflammation-induced tumor, has shed light on the fundamental cellular and molecular aspects of the disease that are to be translated into clinical diagnostics and therapy. Genetic abnormalities including chromosomal translocations involving MALT1 paracaspase, TNFAIP3/A20 inactivation, and MyD88 gain-of-function mutation activate constitutive NF-κB signaling in most MALT lymphomas. Although many novel therapies are being tested in relapsed or aggressive MALT lymphomas, the recently discovered genetic changes underlying the pathogenesis of the disease should provide a mechanistic basis for using specific molecules targeting MALT1 protease and IRAK4 kinase activities in the era of personalized medicine.

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Acknowledgements

This work was supported by grants from the Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness: FIS-PI12/00202 and RTICC-RD12/0036/0063-FEDER (to J.A.M.-C.)

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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46. Coornaert B, Baens M, Heyninck K, et al. T cell antigen receptor stimulation induces MALT1 paracaspase-mediated cleavage of the NF-kappaB inhibitor A20. Nat Immunol 2008; 9:263–271.

47. Staal J, Driege Y, Bekaert T, et al. T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. EMBO J 2011; 30:1742–1752.

48. Rebeaud F, Hailfinger S, Posevitz-Fejfar A, et al. The proteolytic activity of the paracaspase MALT1 is key in T cell activation. Nat Immunol 2008; 9:272–281.

49▪▪. Uehata T, Iwasaki H, Vandenbon A, et al. Malt1-induced cleavage of regnase-1 in CD4(+) helper T cells regulates immune activation. Cell 2013; 153:1036–1049.

This study discovered a novel substrate of Malt1 protease, which induced cleavage of regnase-1 in CD4+ helper T cells to regulate immune activation.

50▪▪. Pelzer C, Cabalzar K, Wolf A, et al. The protease activity of the paracaspase MALT1 is controlled by monoubiquitination. Nat Immunol 2013; 14:337–345.

An elegant study demonstrating that monoubiquitination of MALT1 on Lys644 is essential for its catalytic activation and is, therefore, a potential target for the treatment of ABC-DLBCL and for immunomodulation.

51. Liu H, Ye H, Ruskone-Fourmestraux A, et al. T(11;18) is a marker for all stage gastric MALT lymphomas that will not respond to H. pylori eradication. Gastroenterology 2002; 122:1286–1294.

52. Ye H, Liu H, Attygalle A, et al. Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: significant association with CagA strains of H. pylori in gastric MALT lymphoma. Blood 2003; 102:1012–1018.

53. Choi YJ, Kim N, Paik JH, et al. Characteristics of Helicobacter pylori-positive and Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma and their influence on clinical outcome. Helicobacter 2013; 18:197–205.

54. Toracchio S, Ota H, de Jong D, et al. Translocation t(11;18)(q21;q21) in gastric B-cell lymphomas. Cancer Sci 2009; 100:881–887.

55▪. Li X, Xia B, Guo S, et al. A retrospective analysis of primary gastric diffuse large B-cell lymphoma with or without concomitant mucosa-associated lymphoid tissue (MALT) lymphoma components. Ann Hematol 2013; 92:807–815.

A retrospective study which found that H. pylori infection rates were higher in the gastric DLBCL and MALT lymphomas (75%) than in the de-novo gastric DLBCL group (36%) (P < 0.001), but there were no significant differences in the 5-year PFS and OS estimates for patients with de-novo DLBCL and DLBCL and MALT.

56. Zhou H, Du MQ, Dixit VM. Constitutive NF-kappaB activation by the t(11;18)(q21;q21) product in MALT lymphoma is linked to deregulated ubiquitin ligase activity. Cancer Cell 2005; 7:425–431.

57. Hu S, Du MQ, Park SM, et al. cIAP2 is a ubiquitin protein ligase for BCL10 and is dysregulated in mucosa-associated lymphoid tissue lymphomas. J Clin Invest 2006; 116:174–181.

58▪. Rosebeck S, Rehman AO, Apel IJ, et al. The API2–MALT1 fusion exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling. Oncogene 2013; 10.1038/onc.2013.195. [Epub ahead of print].

This study reports that API2–MALT1 fusion protein exploits TNFR pathway-associated RIP1 ubiquitination to promote oncogenic NF-κB signaling.

59. Rosebeck S, Madden L, Jin X, et al. Cleavage of NIK by the API2–MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation. Science 2011; 331:468–472.

60. Streubel B, Simonitsch-Klupp I, Müllauer L, et al. Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites. Leukemia 2004; 18:1722–1726.

61. Remstein ED, Kurtin PJ, Einerson RR, et al. Primary pulmonary MALT lymphomas show frequent and heterogeneous cytogenetic abnormalities, including aneuploidy and translocations involving API2 and MALT1 and IGH and MALT1. Leukemia 2004; 18:156–160.

62. Hailfinger S, Lenz G, Ngo V, et al. Essential role of MALT1 protease activity in activated B cell-like diffuse large B-cell lymphoma. Proc Natl Acad Sci USA 2009; 106:19946–19951.

63. Ferch U, Kloo B, Gewies A, et al. Inhibition of MALT1 protease activity is selectively toxic for activated B cell-like diffuse large B cell lymphoma cells. J Exp Med 2009; 206:2313–2320.

64. Zhang Q, Siebert R, Yan M, et al. Inactivating mutations and overexpression of BCL10, a caspase recruitment domain-containing gene, in MALT lymphoma with t(1;14)(p22;q32). Nat Genet 1999; 22:63–68.

65. Willis TG, Jadayel DM, Du MQ, et al. Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. Cell 1999; 96:35–45.

66. Ruland J, Duncan GS, Elia A, et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-kappaB and neural tube closure. Cell 2001; 104:33–42.

67. Streubel B, Vinatzer U, Lamprecht A, et al. T(3;14)(p14.1;q32) involving IGH and FOXP1 is a novel recurrent chromosomal aberration in MALT lymphoma. Leukemia 2005; 19:652–658.

68. Wlodarska I, Veyt E, De Paepe P, et al. FOXP1, a gene highly expressed in a subset of diffuse large B-cell lymphoma, is recurrently targeted by genomic aberrations. Leukemia 2005; 19:1299–1305.

69. Sagardoy A, Martinez-Ferrandis JI, Roa S, et al. Downregulation of FOXP1 is required during germinal center B-cell function. Blood 2013; 121:4311–4320.

70. Ansell SM, Akasaka T, McPhail E, et al. t(X;14)(p11;q32) in MALT lymphoma involving GPR34 reveals a role for GPR34 in tumor cell growth. Blood 2012; 120:3949–3957.

71. Baens M, Finalet Ferreiro J, Tousseyn T, et al. t(X;14)(p11.4;q32.33) is recurrent in marginal zone lymphoma and up-regulates GPR34. Haematologica 2012; 97:184–188.

72. Vinatzer U, Gollinger M, Mullauer L, et al. Mucosa-associated lymphoid tissue lymphoma: novel translocations including rearrangements of ODZ2, JMJD2C, and CNN3. Clin Cancer Res 2008; 14:6426–6431.

73. Li ZM, Spagnuolo L, Mensah AA, et al. Gains of CCND3 gene in ocular adnexal MALT lymphomas: an integrated analysis. Br J Haematol 2013; 160:719–722.

74▪. Flossbach L, Holzmann K, Mattfeldt T, et al. High-resolution genomic profiling reveals clonal evolution and competition in gastrointestinal marginal zone B-cell lymphoma and its large cell variant. Int J Cancer 2013; 132:E116–E127.

Using high-resolution SNP microarrays, the authors conclude that diffuse large-cell gastrointestinal lymphomas may evolve from small-cell MALT lymphomas via composite lymphomas as a transition state, undergoing clonal evolution and subclonal competition.

75▪. Vicente-Duenas C, Fontan L, Gonzalez-Herrero I, et al. Expression of MALT1 oncogene in hematopoietic stem/progenitor cells recapitulates the pathogenesis of human lymphoma in mice. Proc Natl Acad Sci USA 2012; 109:10534–10539.

This study characterizes transgenic mice with ectopic expression of MALT1 in hematopoietic stem and progenitor cells that develop human-like MALT lymphomas which showed aggressive transformation to ABC-DLBCL. This study also includes the gene-expression analysis of a large series of biopsies from patients with MALT lymphoma and other B-cell lymphomas.

76. Chng WJ, Remstein ED, Fonseca R, et al. Gene expression profiling of pulmonary mucosa-associated lymphoid tissue lymphoma identifies new biologic insights with potential diagnostic and therapeutic applications. Blood 2009; 113:635–645.

77. Hamoudi RA, Appert A, Ye H, et al. Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism. Leukemia 2010; 24:1487–1497.

78. Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459:712–716.

79. Rinaldi A, Mian M, Chigrinova E, et al. Genome-wide DNA profiling of marginal zone lymphomas identifies subtype-specific lesions with an impact on the clinical outcome. Blood 2011; 117:1595–1604.

80. Chanudet E, Huang Y, Ichimura K, et al. A20 is targeted by promoter methylation, deletion and inactivating mutation in MALT lymphoma. Leukemia 2010; 24:483–487.

81. Bi Y, Zeng N, Chanudet E, et al. A20 inactivation in ocular adnexal MALT lymphoma. Haematologica 2012; 97:926–930.

82. Yan Q, Wang M, Moody S, et al. Distinct involvement of NF-κB regulators by somatic mutation in ocular adnexal malt lymphoma. Br J Haematol 2013; 160:851–854.

83. Liu F, Karube K, Kato H, et al. Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma. Int J Clin Exp Pathol 2012; 5:436–441.

84. Honma K, Tsuzuki S, Nakagawa M, et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood 2009; 114:2467–2475.

85. Schmitz R, Hansmann ML, Bohle V, et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206:981–989.

86. Ngo VN, Young RM, Schmitz R, et al. Oncogenically active MYD88 mutations in human lymphoma. Nature 2011; 470:115–119.

87▪. Li ZM, Rinaldi A, Cavalli A, et al. MYD88 somatic mutations in MALT lymphomas. Br J Haematol 2012; 158:662–664.

This article confirms a previous report [86] and identifies mutations in MYD88 in a small subset of patients with MALT lymphoma.

88▪. Gachard N, Parrens M, Soubeyran I, et al. IGHV gene features and MYD88 L265P mutation separate the three marginal zone lymphoma entities and Waldenström macroglobulinemia/lymphoplasmacytic lymphomas. Leukemia 2013; 27:183–189.

This study shows that MYD88 L265P mutations are preferentially detected in Waldenström macroglobulinemia and lymphoplasmacytic lymphoma patients, and that only a small fraction of marginal zone lymphomas exhibit such MYD88 mutations.

89▪▪. Wang JQ, Jeelall YS, Beutler B, et al. Consequences of the recurrent MYD88L265P somatic mutation for B cell tolerance. J Exp Med 2014; 211:413–426.

MyD88 L265P mutation induced NF-κB-mediated B-cell proliferation that was dependent on continuous upstream Toll-like receptor activation and was rapidly countered by the induction of TNFAIP3/A20 expression.

90. Deutsch AJ, Steinbauer E, Hofmann NA, et al. Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma. Mod Pathol 2013; 26:182–194.

91. Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000; 403:503–511.

92. Ngo VN, Davis RE, Lamy L, et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 2006; 441:106–110.

93. Lenz G, Wright GW, Emre NC, et al. Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proc Natl Acad Sci USA 2008; 105:13520–13525.

94. Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 2009; 459:717–721.

95. Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature 2010; 463:88–92.

96. Lenz G, Davis RE, Ngo VN, et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 2008; 319:1676–1679.

97. Wündisch T, Thiede C, Morgner A, et al. Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication. J Clin Oncol 2005; 23:8018–8024.

98. Nakamura S, Sugiyama T, Matsumoto T, et al. Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan. Gut 2012; 61:507–513.

99▪. Wündisch T, Dieckhoff P, Greene B, et al. Second cancers and residual disease in patients treated for gastric mucosa-associated lymphoid tissue lymphoma by Helicobacter pylori eradication and followed for 10 years. Gastroenterology 2012; 143:936–942.quiz e913–e934.

This study reports that cure of H. pylori infection leads to continuous complete remission in most patients with H. pylori-associated GML, although some patients are at risk for development of secondary cancers (i.e., gastric cancer and non-Hodgkin lymphoma).

100. Ferreri AJ, Ponzoni M, Guidoboni M, et al. Bacteria-eradicating therapy with doxycycline in ocular adnexal MALT lymphoma: a multicenter prospective trial. J Natl Cancer Inst 2006; 98:1375–1382.

101▪. Ferreri AJ, Govi S, Pasini E, et al. Chlamydophila psittaci eradication with doxycycline as first-line targeted therapy for ocular adnexae lymphoma: final results of an international phase II trial. J Clin Oncol 2012; 30:2988–2994.

This phase II clinical trial concludes that upfront doxycycline is a rationale and active treatment for patients with stage I C. psittaci-positive ocular adnexal MALT lymphoma. Lymphoma regression is consequent to C. psittaci eradication, which can easily be monitored on conjunctival and blood samples. Prospective trials aimed at identifying more effective administration schedules for doxycycline are warranted.

102. Kiesewetter B, Raderer M. Antibiotic therapy in nongastrointestinal MALT lymphoma: a review of the literature. Blood 2013; 122:1350–1357.

103. Ruskoné-Fourmestraux A, Fischbach W, Aleman BM, et al. EGILS consensus report. Gastric extranodal marginal zone B-cell lymphoma of MALT. Gut 2011; 60:747–758.

104. Zucca E, Copie-Bergman C, Ricardi U, et al. Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 (Suppl. 6):vi144–vi148.

105▪. Wirth A, Gospodarowicz M, Aleman BM, et al. Long-term outcome for gastric marginal zone lymphoma treated with radiotherapy: a retrospective, multicentre, International Extranodal Lymphoma Study Group study. Ann Oncol 2013; 24:1344–1351.

This retrospective, multicenter study concludes that radiotherapy achieves cure for the majority of patients with low-grade gastric marginal zone lymphoma, including patients who have had prior therapy.

106▪. Olszewski AJ, Castillo JJ. Comparative outcomes of oncologic therapy in gastric extranodal marginal zone (MALT) lymphoma: analysis of the SEER-Medicare database. Ann Oncol 2013; 24:1352–1359.

This observational comparative study found that in elderly patients with stage IE gastric MALT lymphoma, radiotherapy is associated with lower risk of lymphoma-related death than chemotherapy. However, in those requiring systemic treatment, addition of cytotoxic chemotherapy to rituximab in the first-line regimen is not associated with improved survival.

107. Thieblemont C, Coiffier B. Nongastric extranodal marginal zone lymphomas: a challenge in routine practice. Leuk Lymphoma 2008; 49:2229–2230.

108. Bertoni F, Coiffier B, Salles G, et al. MALT lymphomas: pathogenesis can drive treatment. Oncology (Williston Park) 2011; 25:1134–1142.1147.

109▪. Olszewski AJ, Castillo JJ. Survival of patients with marginal zone lymphoma: analysis of the Surveillance, Epidemiology, and End Results database. Cancer 2013; 119:629–638.

The survival for patients with splenic marginal zone lymphoma is similar to that for those with nodal marginal-zone lymphoma (NMZL), and unlike the NMZL and MALT subtypes, it has not improved over the last decade. The prognosis of patients with MALT lymphoma varies according to the anatomical site of origin.

110▪. Kiesewetter B, Troch M, Dolak W, et al. A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma). Haematologica 2013; 98:353–356.

Patients with refractory or relapsed MALT lymphoma require novel therapies. This clinical trial compared the efficacy of diverse novel therapeutic agents in patients with MALT lymphoma, including lenalidomide, rituximab with either cladribine, fludarabine, bendamustine, or chlorambucil, and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and PI3K inhibitors. Most therapeutic regimens showed promising results for the majority of patients.

111▪. Troch M, Kiesewetter B, Willenbacher W, et al. Rituximab plus subcutaneous cladribine in patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue: a phase II study by the Arbeitsgemeinschaft Medikamentose Tumortherapie. Haematologica 2013; 98:264–268.

Patients with refractory or relapsed MALT lymphoma require novel therapies. This clinical trial compared the efficacy of diverse novel therapeutic agents in patients with MALT lymphoma, including lenalidomide, rituximab with either cladribine, fludarabine, bendamustine, or chlorambucil, and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and PI3K inhibitors. Most therapeutic regimens showed promising results for the majority of patients.

112▪. Salar A, Domingo-Domenech E, Estany C, et al. Combination therapy with rituximab and intravenous or oral fludarabine in the first-line, systemic treatment of patients with extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue type. Cancer 2009; 115:5210–5217.

Patients with refractory or relapsed MALT lymphoma require novel therapies. This clinical trial compared the efficacy of diverse novel therapeutic agents in patients with MALT lymphoma, including lenalidomide, rituximab with either cladribine, fludarabine, bendamustine, or chlorambucil, and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and PI3K inhibitors. Most therapeutic regimens showed promising results for the majority of patients.

113▪. Kiesewetter B, Mayerhoefer ME, Lukas J, et al. Rituximab plus bendamustine is active in pretreated patients with extragastric marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma). Ann Hematol 2014; 93:249–253.

Patients with refractory or relapsed MALT lymphoma require novel therapies. This clinical trial compared the efficacy of diverse novel therapeutic agents in patients with MALT lymphoma, including lenalidomide, rituximab with either cladribine, fludarabine, bendamustine, or chlorambucil, and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and PI3K inhibitors. Most therapeutic regimens showed promising results for the majority of patients.

114▪. Zucca E, Conconi A, Laszlo D, et al. Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 Randomized Study. J Clin Oncol 2013; 31:565–572.

Patients with refractory or relapsed MALT lymphoma require novel therapies. This clinical trial compared the efficacy of diverse novel therapeutic agents in patients with MALT lymphoma, including lenalidomide, rituximab with either cladribine, fludarabine, bendamustine, or chlorambucil, and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and PI3K inhibitors. Most therapeutic regimens showed promising results for the majority of patients.

115▪. Fanale M, Assouline S, Kuruvilla J, et al. Phase IA/II, multicentre, open-label study of the CD40 antagonistic monoclonal antibody lucatumumab in adult patients with advanced non-Hodgkin or Hodgkin lymphoma. Br J Haematol 2014; 164:258–265.

Patients with refractory or relapsed MALT lymphoma require novel therapies. This clinical trial compared the efficacy of diverse novel therapeutic agents in patients with MALT lymphoma, including lenalidomide, rituximab with either cladribine, fludarabine, bendamustine, or chlorambucil, and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and PI3K inhibitors. Most therapeutic regimens showed promising results for the majority of patients.

116▪. Joshi M, Sheikh H, Abbi K, et al. Marginal zone lymphoma: old, new, targeted, and epigenetic therapies. Ther Adv Hematol 2012; 3:275–290.

Patients with refractory or relapsed MALT lymphoma require novel therapies. This clinical trial compared the efficacy of diverse novel therapeutic agents in patients with MALT lymphoma, including lenalidomide, rituximab with either cladribine, fludarabine, bendamustine or chlorambucil, and other new agents such as the antagonistic CD40 monoclonal antibody lucatumumab, everolimus, vorinostat, and PI3K inhibitors. Most therapeutic regimens showed promising results for the majority of patients.

117▪▪. Fontan L, Yang C, Kabaleeswaran V, et al. MALT1 small molecule inhibitors specifically suppress ABC-DLBCL in vitro and in vivo. Cancer Cell 2012; 22:812–824.

By using in-vitro MALT1 protease assays in high-throughput screens of small-molecule libraries, two groups have found inhibitors of MALT1 activity. Fontan et al. discovered a novel small molecule termed MI-2 that inhibited MALT1 at low micromolar concentrations by forming an irreversible covalent linkage in the active site. Nagel et al. identified that phenothiazines, used as antipsychotic drugs, can inhibit MALT1 proteolytic activity through reversible binding in a pocket located opposite to the paracaspase active site. Both MI-2 and the phenothiazines were selectively toxic to ABC-DLBCL cells in vitro and in vivo.

118▪▪. Nagel D, Spranger S, Vincendeau M, et al. Pharmacologic inhibition of MALT1 protease by phenothiazines as a therapeutic approach for the treatment of aggressive ABC-DLBCL. Cancer Cell 2012; 22:825–837.

By using in-vitro MALT1 protease assays in high-throughput screens of small-molecule libraries, two groups have found inhibitors of MALT1 activity. Fontan et al. discovered a novel small molecule termed MI-2 that inhibited MALT1 at low micromolar concentrations by forming an irreversible covalent linkage in the active site. Nagel et al. identified that phenothiazines, used as antipsychotic drugs, can inhibit MALT1 proteolytic activity through reversible binding in a pocket located opposite to the paracaspase active site. Both MI-2 and the phenothiazines were selectively toxic to ABC-DLBCL cells in vitro and in vivo.

119. Schlauderer F, Lammens K, Nagel D, et al. Structural analysis of phenothiazine derivatives as allosteric inhibitors of the MALT1 paracaspase. Angew Chem Int Ed Engl 2013; 52:10384–10387.

120. Wang Z, Wesche H, Stevens T, et al. IRAK-4 inhibitors for inflammation. Curr Top Med Chem 2009; 9:724–737.

121. Tsai AG, Lu Z, Lieber MR. The t(14;18)(q32;q21)/IGH-MALT1 translocation in MALT lymphomas is a CpG-type translocation, but the t(11;18)(q21;q21)/API2–MALT1 translocation in MALT lymphomas is not. Blood 2010; 115:3640–3641.author reply 3641–3642.

122. Baens M, Fevery S, Sagaert X, et al. Selective expansion of marginal zone B cells in Emicro–API2–MALT1 mice is linked to enhanced IkappaB kinase gamma polyubiquitination. Cancer Res 2006; 66:5270–5277.

123. Li Z, Wang H, Xue L, et al. E{micro}-BCL10 mice exhibit constitutive activation of both canonical and noncanonical NF-{kappa}B pathways generating marginal zone (MZ) B cell expansion as a precursor to splenic MZ lymphoma. Blood 2009; 114:4158–4168.

124. Yoneda T, Imaizumi K, Maeda M, et al. Regulatory mechanisms of TRAF2-mediated signal transduction by Bcl10, a MALT lymphoma-associated protein. J Biol Chem 2000; 275:11114–11120.

125. Kikushige Y, Ishikawa F, Miyamoto T, et al. Self-renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 2011; 20:246–259.

126. Quivoron C, Couronne L, Della Valle V, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell 2011; 20:25–38.

127. Martinez-Climent JA, Fontan L, Gascoyne RD, et al. Lymphoma stem cells: enough evidence to support their existence? Haematologica 2010; 95:293–302.

Keywords:

chronic inflammation; MALT lymphoma; MALT1 paracaspase; NF-κB; TNFAIP3/A20

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