Gene Summary

Gene:MALT1; MALT1 paracaspase
Aliases: MLT, MLT1, IMD12, PCASP1
Summary:This gene encodes a caspase-like protease that plays a role in BCL10-induced activation of NF-kappaB. The protein is a component of the CARMA1-BCL10-MALT1 (CBM) signalosome that triggers NF-kappaB signaling and lymphoctye activation following antigen-receptor stimulation. Mutations in this gene result in immunodeficiency 12 (IMD12). This gene has been found to be recurrently rearranged in chromosomal translocations with other genes in mucosa-associated lymphoid tissue lymphomas, including a t(11;18)(q21;q21) translocation with the baculoviral IAP repeat-containing protein 3 (also known as apoptosis inhibitor 2) locus [BIRC3(API2)-MALT1], and a t(14;18)(q32;q21) translocation with the immunoglobulin heavy chain locus (IGH-MALT1). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, May 2018]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:mucosa-associated lymphoid tissue lymphoma translocation protein 1
Source:NCBIAccessed: 30 August, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 30 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosome 18
  • Chromosome 14
  • Neoplasm Proteins
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • fas Receptor
  • Young Adult
  • Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein
  • Transcription
  • Caspases
  • NF-kappa B
  • Promoter Regions
  • BIRC3
  • World Health Organization
  • Signal Transducing Adaptor Proteins
  • B-Cell CLL-Lymphoma 10 Protein
  • MALT Lymphoma
  • Translocation
  • Oncogene Fusion Proteins
  • BCL2 protein
  • BAD
  • Lung Cancer
  • bcl-2-Associated X Protein
  • Virulence
  • B-Cell Lymphoma
  • Up-Regulation
  • MALT1
  • Single Nucleotide Polymorphism
  • Transcription Factor RelA
  • FISH
  • X-Ray Computed Tomography
  • Zinc Fingers
  • Ubiquitin-Protein Ligases
  • Protease Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Receptors, Antigen
  • Stomach Cancer
  • Diffuse Large B-Cell Lymphoma
  • Skin Cancer
  • Trisomy
  • Sequence Homology
  • Sequence Deletion
  • Chromosome 11
Tag cloud generated 30 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MALT1 (cancer-related)

Toyoda K, Maeshima AM, Nomoto J, et al.
Mucosa-associated lymphoid tissue lymphoma with t(11;18)(q21;q21) translocation: long-term follow-up results.
Ann Hematol. 2019; 98(7):1675-1687 [PubMed] Related Publications
Translocation (11;18)(q21;q21) is found in mucosa-associated lymphoid tissue (MALT) lymphoma, resulting in API2/MALT1 gene fusion. It is known that t(11;18)-positive MALT lymphoma shows a tendency to disseminate and be resistant to Helicobacter pylori eradication by antibiotics. However, the prognostic features including recurrence and histological transformation (HT) remain unknown. We conducted a single-institute retrospective analysis of 464 patients with newly diagnosed MALT lymphoma, evaluating the impact of t(11;18) on clinical outcomes. One hundred and six patients were screened for the translocation by fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. Of these patients, 26 patients (25%) were diagnosed as MALT lymphoma with t(11;18). The patients had a significantly shortened progression-free survival (PFS at 10 years; 26% v 57%; P = 0.004) compared to those without t(11;18). However, this did not translate into overall survival or incidence of HT. We confirmed previous reports stating that t(11;18)-positive MALT lymphoma showed disseminated disease and refractoriness to H. pylori eradication therapy. Patients with t(11;18) had more frequent monoclonal gammopathy, especially of IgM subtype (31% v 8%; P = 0.008), some of which developed class switch. These findings characterize the features of t(11;18)-positive MALT lymphoma, suggesting that it comprises a distinct clinical entity of MALT lymphoma.

Magnoli F, Bernasconi B, Vivian L, et al.
Primary extranodal diffuse large B-cell lymphomas: Many sites, many entities? Clinico-pathological, immunohistochemical and cytogenetic study of 106 cases.
Cancer Genet. 2018; 228-229:28-40 [PubMed] Related Publications
We analyzed the clinicopathological, immunohistochemical and cytogenetic features of 106 extranodal (EN) diffuse large B-cell lymphomas (DLBCLs) from stomach (34 cases), intestine (10), cervico-cephalic region (11), central nervous system (13), testes (21), skin (8), and miscellaneous sites (9). Hans' algorithm and the immunohistochemical double expressor score (DES) for MYC and BCL2 were applied to all cases. A subset of fifty-eight cases were analyzed with fluorescent in situ hybridization (FISH) with specific break apart probes for BCL6, MYC, BCL2, CCND1, BCL10 and MALT1 genes. Clinical records were available for all patients. The immunohistochemical study showed that, in our series of EN-DLBCLs, the Hans' subgroup and the DES differed significantly according to the site of origin. At FISH analysis, BCL6 and BCL2 were the most commonly rearranged genes in non-GC and in GC cases, respectively. Gastrointestinal lymphomas displayed the highest rate of gene rearrangements, often with MYC involvement. One testicular DLBCL showed BCL2/MYC double hit. At survival analysis, cerebral and testicular origin was associated with poor prognosis. In addition, Hans' subgroup and other immunohistochemical markers influenced patients' outcome. In conclusion, our data suggest that immunophenotypic, genetic and survival characteristics of EN-DLBCL are related to the specific primary site of the disease.

Akasaka T, Kishimori C, Maekawa F, et al.
Pulmonary extranodal marginal zone lymphoma that presented with macroglobulinemia and marked plasmacytic cell proliferation carrying the t(14;18)(q32;q21)/MALT1-immunoglobulin heavy-chain fusion gene in pleural fluid.
J Clin Exp Hematop. 2018; 58(3):141-147 [PubMed] Free Access to Full Article Related Publications
An 80-year-old man presented with the accumulation of pleural fluid in the right thoracic cavity. Serum electrophoresis revealed an M-component and immunofixation confirmed IgM/λ. The level of IgM was 1,526 mg/dL. Imaging studies showed an infiltrative condition of the ipsilateral lung parenchyma. The fluid contained abundant neoplastic cells with the morphological and immunophenotypic features of plasma cells, which expressed IgM/λ monoclonal immunoglobulins on the cell surface and in the cytoplasm. The karyotype was 48,XY,+3,add(9)(p13),+12,add(14)(q32),del(16)(q22),-18,+mar, and a series of fluorescence in situ hybridization studies demonstrated that the add(14) chromosome represented der(14)t(14;18)(q32;q21), at which the MALT1-immunoglobulin heavy-chain (IGH) fusion gene was localized. A long-distance polymerase chain reaction amplified the fragment encompassing the two genes, showing that the junction occurred at the J6 segment of IGH and 3.7-kb upstream of the MALT1 breakpoint cluster. We propose that this case represents an extreme form of the plasmacytic differentiation of extranodal marginal zone lymphoma that developed in the lung.

Phelan JD, Young RM, Webster DE, et al.
A multiprotein supercomplex controlling oncogenic signalling in lymphoma.
Nature. 2018; 560(7718):387-391 [PubMed] Free Access to Full Article Related Publications
B cell receptor (BCR) signalling has emerged as a therapeutic target in B cell lymphomas, but inhibiting this pathway in diffuse large B cell lymphoma (DLBCL) has benefited only a subset of patients

Hyeon J, Lee B, Shin SH, et al.
Targeted deep sequencing of gastric marginal zone lymphoma identified alterations of TRAF3 and TNFAIP3 that were mutually exclusive for MALT1 rearrangement.
Mod Pathol. 2018; 31(9):1418-1428 [PubMed] Related Publications
Gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue is a distinct entity in that Helicobacter pylori infection plays the most important causative role in the development of the disease. To investigate the genomic alteration in gastric marginal zone lymphoma that was resistant to the H. pylori eradication therapy, we analyzed 19 cases of the gastric marginal zone lymphoma using fluorescence in situ hybridization for MALT1, BCL10 rearrangement, and targeted sequencing using an Illumina platform. Major genetic alterations affected genes involved in nuclear factor (NF)-κB pathway activation and included MALT1 rearrangement (39%), and somatic mutations of TRAF3 (21%), TNFAIP3 (16%), and NOTCH1 (16%). In the MALT1 rearrangement-negative group, disruptive somatic mutations of TRAF3 were the most common alterations (4/12, 33%), followed by somatic mutations of TNFAIP3 (3/12, 25%), and NOTCH1 (3/12, 25%). The present study confirms that genes involved in activation of NF-κB-signaling pathways are a major driver in oncogenesis of H. pylori eradication-resistant gastric marginal zone lymphoma and revealed that TRAF3 mutation is a major contributor in MALT1 rearrangement-negative gastric marginal zone lymphoma.

Wei X, Qi Y, Jia N, et al.
Hyperbaric oxygen treatment sensitizes gastric cancer cells to melatonin-induced apoptosis through multiple pathways.
J Cell Biochem. 2018; 119(8):6723-6731 [PubMed] Related Publications
Although extensive efforts have been made in recent decades to treat advanced gastric cancer with comprehensive therapy based on chemotherapy, effective anti-gastric cancer therapeutics are still lacking in the clinics. Therefore, potent novel anti-gastric cancer ways are greatly needed. Here, we explored hyperbaric oxygen treatment as a novel and effective adjuvant treatment method which has anti-gastric cancer effects when used together with melatonin. When performed together with MLT, HBO effectively inhibited tumorigenicity of gastric cancer through selectively inducing a robust tumor suppressive apoptosis response. Mechanistic studies revealed that the sensitizing effect of hyperbaric oxygen is due to decreased ratio of Bcl-2/Bax, increased level of p53, cleaved Caspase3, GRP78, CHOP, and LC3. These results give a vivid picture that classic apoptosis pathways including mitochondrial pathway, tumor suppressive endoplasmic reticulum stress (ERS), and autophagy are all involved in the process. From the preliminary results got from the current study, we identified that HBO sensitizes human gastric cancer cells to MLT-induced apoptosis through a variety of complicated molecular mechanisms. HBO may provide a novel candidate supplemental treatment method for further development of potential anti-gastric cancer therapeutics. The combination of HBO and MLT could be a promising treatment for advanced gastric cancer.

Twa DDW, Mottok A, Savage KJ, Steidl C
The pathobiology of primary testicular diffuse large B-cell lymphoma: Implications for novel therapies.
Blood Rev. 2018; 32(3):249-255 [PubMed] Related Publications
Primary testicular lymphomas (PTL) are the most prevalent type of testicular cancer arising in men over the age of 60. PTL accounts for approximately 1-2% of all non-Hodgkin lymphomas and most present with localized disease but despite this, outcome is poor. The majority of cases represent an extranodal manifestation of diffuse large B-cell lymphoma (DLBCL), known as primary testicular DLBCL (PT-DLBCL). Gene expression profiling has established that over 75% of PT-DLBCLs resemble the activated B-cell-like (ABC) or non-germinal center subtype of nodal DLBCL. In distilling the specific mutational landscape and immunophenotypic profiles, immune-escape and sustained signalling emerge as prominent features of PT-DLBCL. These include genomic alterations arising within the core components of antigen presentation (CIITA, B2M, and HLA loci) and structural rearrangements of programmed death ligands 1 (CD274) and 2 (PDCD1LG2). Enrichment for somatic mutations within NF-κB pathway genes (MYD88, CD79B, NFKBIZ, BCL10, and MALT1) also feature prominently in PT-DLBCL. Taken together, the unique molecular and clinical characteristics of PT-DLBCL have informed on aspects of the distinct disease biology of this organotypic lymphoma that may guide rational therapeutic strategies.

Ekambaram P, Lee JL, Hubel NE, et al.
The CARMA3-Bcl10-MALT1 Signalosome Drives NFκB Activation and Promotes Aggressiveness in Angiotensin II Receptor-Positive Breast Cancer.
Cancer Res. 2018; 78(5):1225-1240 [PubMed] Free Access to Full Article Related Publications
The angiotensin II receptor AGTR1, which mediates vasoconstrictive and inflammatory signaling in vascular disease, is overexpressed aberrantly in some breast cancers. In this study, we established the significance of an AGTR1-responsive NFκB signaling pathway in this breast cancer subset. We documented that AGTR1 overexpression occurred in the luminal A and B subtypes of breast cancer, was mutually exclusive of HER2 expression, and correlated with aggressive features that include increased lymph node metastasis, reduced responsiveness to neoadjuvant therapy, and reduced overall survival. Mechanistically, AGTR1 overexpression directed both ligand-independent and ligand-dependent activation of NFκB, mediated by a signaling pathway that requires the triad of CARMA3, Bcl10, and MALT1 (CBM signalosome). Activation of this pathway drove cancer cell-intrinsic responses that include proliferation, migration, and invasion. In addition, CBM-dependent activation of NFκB elicited cancer cell-extrinsic effects, impacting endothelial cells of the tumor microenvironment to promote tumor angiogenesis. CBM/NFκB signaling in AGTR1

Iwamuro M, Takenaka R, Nakagawa M, et al.
Management of gastric mucosa-associated lymphoid tissue lymphoma in patients with extra copies of the
World J Gastroenterol. 2017; 23(33):6155-6163 [PubMed] Free Access to Full Article Related Publications
AIM: To identify the clinical features of gastric mucosa-associated lymphoid tissue (MALT) lymphoma with extra copies of MALT1.
METHODS: This is a multi-centered, retrospective study. We reviewed 146 patients with MALT lymphoma in the stomach who underwent fluorescence in situ hybridization analysis for t(11;18) translocation. Patients were subdivided into patients without t(11;18) translocation or extra copies of MALT1 (Group A, n = 88), patients with t(11;18) translocation (Group B, n = 27), and patients with extra copies of MALT1 (Group C, n = 31). The clinical background, treatment, and outcomes of each group were investigated.
RESULTS: Groups A and C showed slight female predominance, whereas Group B showed slight male predominance. Mean ages and clinical stages at lymphoma diagnosis were not different between groups. Complete response was obtained in 61 patients in Group A (69.3%), 22 in Group B (81.5%), and 21 in Group C (67.7%). Helicobacter pylori (H. pylori) eradication alone resulted in complete remission in 44 patients in Group A and 13 in Group C. In Group B, 14 patients underwent radiotherapy alone, which resulted in lymphoma disappearance. Although the difference was not statistically significant, event-free survival in Group C tended to be inferior to that in Group A (P = 0.10).
CONCLUSION: Patients with t(11;18) translocation should be treated differently from others. Patients with extra copies of MALT1 could be initially treated with H. pylori eradication, similar to patients without t(11;18) translocation or extra copies of MALT1.

Fic M, Gomulkiewicz A, Grzegrzolka J, et al.
The Impact of Melatonin on Colon Cancer Cells' Resistance to Doxorubicin in an in Vitro Study.
Int J Mol Sci. 2017; 18(7) [PubMed] Free Access to Full Article Related Publications
Multi-drug resistance (MDR) is the main cause of low effectiveness of cancer chemotherapy. P-glycoprotein (P-gp) is one of the main factors determining MDR. Some studies indicate the potential role of melatonin (MLT) in MDR. In this study, we examined the effect of MLT on colon cancer cell's resistance to doxorubicin (DOX). Using the sulforhodamine B (SRB), method the effect of tested substances on the survival of LoVo (colon cancer cells sensitive to DOX) and LoVo

Zubidat AE, Haim A
Artificial light-at-night - a novel lifestyle risk factor for metabolic disorder and cancer morbidity.
J Basic Clin Physiol Pharmacol. 2017; 28(4):295-313 [PubMed] Related Publications
Both obesity and breast cancer are already recognized worldwide as the most common syndromes in our modern society. Currently, there is accumulating evidence from epidemiological and experimental studies suggesting that these syndromes are closely associated with circadian disruption. It has been suggested that melatonin (MLT) and the circadian clock genes both play an important role in the development of these syndromes. However, we still poorly understand the molecular mechanism underlying the association between circadian disruption and the modern health syndromes. One promising candidate is epigenetic modifications of various genes, including clock genes, circadian-related genes, oncogenes, and metabolic genes. DNA methylation is the most prominent epigenetic signaling tool for gene expression regulation induced by environmental exposures, such as artificial light-at-night (ALAN). In this review, we first provide an overview on the molecular feedback loops that generate the circadian regulation and how circadian disruption by ALAN can impose adverse impacts on public health, particularly metabolic disorders and breast cancer development. We then focus on the relation between ALAN-induced circadian disruption and both global DNA methylation and specific loci methylation in relation to obesity and breast cancer morbidities. DNA hypo-methylation and DNA hyper-methylation, are suggested as the most studied epigenetic tools for the activation and silencing of genes that regulate metabolic and monostatic responses. Finally, we discuss the potential clinical and therapeutic roles of MLT suppression and DNA methylation patterns as novel biomarkers for the early detection of metabolic disorders and breast cancer development.

Volk-Draper LD, Hall KL, Wilber AC, Ran S
Lymphatic endothelial progenitors originate from plastic myeloid cells activated by toll-like receptor-4.
PLoS One. 2017; 12(6):e0179257 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Myeloid-derived lymphatic endothelial cells (M-LECP) are induced by inflammation and play an important role in adult lymphangiogenesis. However, the mechanisms driving M-LECP differentiation are currently unclear. We previously showed that activation of Toll-like receptor-4 (TLR4) induces myeloid-lymphatic transition (MLT) of immortalized mouse myeloid cells. Here the goals were to assess the potential of different TLR4 ligands to induce pro-lymphatic reprogramming in human and mouse primary myeloid cells and to identify transcriptional changes regulating this process.
METHODOLOGY/PRINCIPAL FINDINGS: Human and mouse myeloid cells were reprogrammed to the lymphatic phenotype by TLR4 ligands including lipopolysaccharide (LPS), recombinant high mobility group box 1 protein (HMGB1), and paclitaxel. TLR4 induced similar MLT in cells from mice of different strains and immune status. Commonly induced genes were detected by transcriptional profiling in human and mouse myeloid cells from either immunocompetent or immunodeficient mice. Shared trends included: (1) novel expression of lymphatic-specific markers vascular endothelial growth factor receptor-3 (VEGFR-3), lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) and podoplanin (PDPN) largely absent prior to induction; (2) lack of notable changes in blood vessel-specific markers; (3) transient expression of VEGFR-3, but sustained increase of vascular endothelial growth factor-C (VEGF-C) and a variety of inflammatory cytokines; (4) dependency of VEGFR-3 upregulation and other LEC genes on NF-κB; and (5) novel expression of lymphatic-specific (e.g., PROX1) and stem/progenitor (e.g., E2F1) transcription factors known for their roles in adult and embryonic vascular formation. M-LECP generated by TLR4 ligands in vitro were functional in vivo as demonstrated by significantly increased lymphatic vessel density and lymphatic metastasis detected in orthotopic breast cancer models.
CONCLUSIONS/SIGNIFICANCE: We established a novel TLR4-dependent protocol for in vitro production of functionally competent M-LECP from primary human or mouse myeloid cells and identified many potential regulators of this process. This information can be further exploited for research and therapeutic purposes.

Yang F, Liu X, Liu Y, et al.
miR-181d/MALT1 regulatory axis attenuates mesenchymal phenotype through NF-κB pathways in glioblastoma.
Cancer Lett. 2017; 396:1-9 [PubMed] Related Publications
The mesenchymal (MES) subtype of glioblastoma (GBM) indicated a more malignant phenotype and worse prognosis compared with their proneural (PN) counterpart. The plasticity between PN and MES transcriptome signatures provided an approach for clinical intervention. However, few miRNAs have been identified to participate in the shift between subtypes. Here, we utilized transcriptomic data and experimental evidences to prove that miR-181d was a novel regulator of NFκB signaling pathway by directly repressing MALT1, leading to induced PN markers and reduced MES genes. Functionally, ectopic expression of miR-181d suppressed GBM cell proliferation, colony formation and anchor-independent growth, as well as migration, invasion and tube formation. Moreover, miR-181d overexpression increased radio- and chemo-sensitivity for GBM cells. Rescue of MALT1 could partially reverse the effects of miR-181d in GBM malignant behaviors. Clinically, miR-181d could serve as a prognostic indicator for GBM patients. Taken together, we concluded that loss of miR-181d contributes to aggressive biological processes associated with MES phenotype via NFκB signaling, which broaden our insights into the underlying mechanisms in subtype transition and miRNA-based tailored medicine for GBM management.

Dai B, Grau M, Juilland M, et al.
B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma.
Blood. 2017; 129(3):333-346 [PubMed] Related Publications
Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of B-cell receptor (BCR) signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 complex that links BCR signaling to the NF-κB pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls an MYC-driven gene expression network predominantly through increasing MYC protein stability. Thus, our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1-induced MYC regulation is not restricted to MCL, but represents a common mechanism. MYC itself is pivotal for MCL survival because its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy of targeting the MALT1-MYC axis in MCL patients.

Bonsignore L, Passelli K, Pelzer C, et al.
A role for MALT1 activity in Kaposi's sarcoma-associated herpes virus latency and growth of primary effusion lymphoma.
Leukemia. 2017; 31(3):614-624 [PubMed] Free Access to Full Article Related Publications
Primary effusion lymphoma (PEL) is an incurable malignancy that develops in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpes virus (KSHV). Malignant growth of KSHV-infected B cells requires the activity of the transcription factor nuclear factor (NF)-κB, which controls maintenance of viral latency and suppression of the viral lytic program. Here we show that the KSHV proteins K13 and K15 promote NF-κB activation via the protease mucosa-associated lymphoid tissue lymphoma translocation protein-1 (MALT1), a key driver of NF-κB activation in lymphocytes. Inhibition of the MALT1 protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALT1 in PEL, and provide a rationale for the pharmacological targeting of MALT1 in PEL therapy.

Wang S, Clarke PAG, Davis R, et al.
Sex steroid-induced DNA methylation changes and inflammation response in prostate cancer.
Cytokine. 2016; 86:110-118 [PubMed] Related Publications
BACKGROUND: Sex steroid hormones have been reported to induce inflammation causing dysregulation of cytokines in prostate cancer cells. However, the underlying epigenetic mechanism has not well been studied. The objective of this study was to evaluate the effect of sex steroid hormones on epigenetic DNA methylation changes in prostate cancer cells using a signature PCR methylation array panel that correspond to 96 genes with biological function in the human inflammatory and autoimmune signals in prostate cancer. Of the 96-gene panel, 32 genes showed at least 10% differentially methylation level in response to hormonal treatment when compared to untreated cells. Genes that were hypomethylated included CXCL12, CXCL5, CCL25, IL1F8, IL13RAI, STAT5A, CXCR4 and TLR5; and genes that were hypermethylated included ELA2, TOLLIP, LAG3, CD276 and MALT1. Quantitative RT-PCR analysis of select genes represented in a cytokine expression array panel showed inverse association between DNA methylation and gene expression for TOLLIP, CXCL5, CCL18 and IL5 genes and treatment of prostate cancer cells with 5'-aza-2'-deoxycytidine with or without trichostatin A induced up-regulation of TOLLIP expression. Further analysis of relative gene expression of matched prostate cancer tissues when compared to benign tissues from individual patients with prostate cancer showed increased and significant expression for CCL18 (2.6-fold; p<0.001), a modest yet significant increase in IL5 expression (1.17-fold; p=0.015), and a modest increase in CXCL5 expression (1.4-fold; p=0.25). In conclusion, our studies demonstrate that sex steroid hormones can induce aberrant gene expression via differential methylation changes in prostate carcinogenesis.

Vallois D, Dobay MP, Morin RD, et al.
Activating mutations in genes related to TCR signaling in angioimmunoblastic and other follicular helper T-cell-derived lymphomas.
Blood. 2016; 128(11):1490-502 [PubMed] Related Publications
Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas.

Otto C, Scholtysik R, Schmitz R, et al.
Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas.
Genes Chromosomes Cancer. 2016; 55(12):932-943 [PubMed] Related Publications
Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners. Moreover, we studied eight DLBCL with MYC translocations not involving IG or known non-IG loci as translocation partner to search for novel MYC translocations. We identified three novel IGH-associated translocations. Chromosomal breakpoints involved the IMMP2L gene in 7q31, the BCAS2 gene in 1p13, and the PVRL2 gene in 19q13. The latter gene, which is recurrently translocated in T-cell lymphomas, is significantly higher expressed in the biopsy with the translocation compared to cases without this genetic aberration, indicating a pathogenetic role of PVRL2 also in DLBCL. In one case with a MYC break we obtained a novel MYC-SOCS1 translocation representing an unusual translocation of a proto-oncogene with a tumor suppressor gene. Indeed, we demonstrate that the oncogene was deregulated and the tumor suppressor gene inactivated. As both genes undergo aberrant somatic hypermutation in the region of the chromosomal breakpoints, this translocation likely happened as a byproduct of the hypermutation process. Overall, our study suggests that chromosomal translocations in DLBCL are more heterogeneous than previously known. © 2016 Wiley Periodicals, Inc.

Yang W, Li Y, Li P, Wang L
PMA/IONO affects diffuse large B-cell lymphoma cell growth through upregulation of A20 expression.
Oncol Rep. 2016; 36(2):1069-75 [PubMed] Related Publications
Diffuse large B-cell lymphoma (DLBCL) is a common non-Hodgkin lymphoma. A20 and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) are known to be related to DLBCL pathogenesis and progression. This study aimed to assess the effects of phorbol myristate acetate/ionomycin (PMA/IONO) on the growth and apoptosis of the DLBCL cell line OCI-LY1, and their associations with A20, MALT1 and survivin levels. Cell viability was assessed by MTT assay. Cell cycle distribution and apoptosis were evaluated using flow cytometry after incubation with Annexin V-FITC/propidium iodide (PI) and RNase/PI, respectively. Gene and protein expression levels were determined by quantitative real-time PCR and western blotting, respectively. To further determine the role of A20, this gene was silenced in the OCI-LY1 cell line by specific siRNA transfection. A20 protein levels were higher in the OCI-LY1 cells treated with PMA/IONO compared with the controls, and were positively correlated with the concentration and treatment time of IONO, but not with changes of PMA and MALT1. Meanwhile, survivin expression was reduced in the OCI-LY1 cells after PMA/IONO treatment. In addition, OCI-LY1 proliferation was markedly inhibited, with a negative correlation between cell viability and IONO concentration. In concordance, apoptosis rates were higher in the OCI-LY1 cells after PMA + IONO treatment. Cell cycle distribution differed between the OCI-LY1 cells with and without PMA/IONO treatment only at 24 h, with increased cells in the G0/G1 stage after PMA/IONO treatment. These findings indicate that PMA/IONO promotes the apoptosis and inhibits the growth of DLBCL cells, in association with A20 upregulation. Thus, A20 may be a potential therapeutic target for DLBCL.

Bennett JA, Oliva E, Nardi V, et al.
Primary Endometrial Marginal Zone Lymphoma (MALT Lymphoma): A Unique Clinicopathologic Entity.
Am J Surg Pathol. 2016; 40(9):1217-23 [PubMed] Related Publications
Primary lymphoma of the endometrium is exceptionally rare. Several cases of distinctly nodular lymphoid proliferations confined to the endometrium have previously been described and reported as lymphomas of mucosa-associated lymphoid tissue (MALT). We report the largest series (n=8) of these lymphomas, further defining their morphologic, immunohistochemical, and molecular spectrum. Patients ranged in age from 50 to 87 (median, 62) years. None had a prior history of lymphoma, and lesions were incidental in all but 1 in which a polyp was noted on macroscopic examination. Nodules ranged from small, round, and uniform with minimal architectural effacement to large, expansile, and coalescing with foci of diffuse growth. In the majority, the nodules were confined to the endometrium; however, 2 cases showed myometrial involvement, 1 of which also had extensive extrauterine disease. The nodules comprised monomorphic populations of mature CD20 B lymphocytes with pale scant cytoplasm, CD43, BCL2, and IgM coexpression, and absence of CD10, CD23, and IgD expression. The nodules were associated with CD21/CD23 follicular dendritic meshworks. Clonality was detected in 6 lesions, in 4 by polymerase chain reaction for clonal IGH rearrangement and in 3 by in situ hybridization for immunoglobulin light chains. All were negative for IGH and MALT1 rearrangements by fluorescence in situ hybridization. None of the patients received additional therapy after resection, and most (7/8) are alive with no evidence of disease at last follow-up (mean 4.2 y), whereas the remaining patient is alive with stable disease. These findings demonstrate the unique clinical and pathologic features that characterize primary MALT lymphoma of the endometrium.

Ganapathi KA, Jobanputra V, Iwamoto F, et al.
The genetic landscape of dural marginal zone lymphomas.
Oncotarget. 2016; 7(28):43052-43061 [PubMed] Free Access to Full Article Related Publications
The dura is a rare site of involvement by marginal zone lymphoma (MZL) and the biology of dural MZL is not well understood. We performed genome-wide DNA copy number and targeted mutational analysis of 14 dural MZL to determine the genetic landscape of this entity. Monoallelic and biallelic inactivation of TNFAIP3 by mutation (n=5) or loss (n=1) was observed in 6/9 (67%) dural MZL exhibiting plasmacytic differentiation, including 3 IgG4+ cases. In contrast, activating NOTCH2 mutations were detected in 4/5 (80%) dural MZL displaying variable monocytoid morphology. Inactivating TBL1XR1 mutations were identified in all NOTCH2 mutated cases. Recurrent mutations in KLHL6 (n=2) and MLL2 (n=2) were also detected. Gains at 6p25.3 (n=2) and losses at 1p36.32 (n=3) were common chromosomal imbalances, with loss of heterozygosity (LOH) of these loci observed in a subset of cases. Translocations involving the IGH or MALT1 genes were not identified. Our results indicate genetic similarities between dural MZL and other MZL subtypes. However, recurrent and mutually exclusive genetic alterations of TNFAIP3 and NOTCH2 appear to be associated with distinct disease phenotypes in dural MZL.

Juilland M, Thome M
Role of the CARMA1/BCL10/MALT1 complex in lymphoid malignancies.
Curr Opin Hematol. 2016; 23(4):402-9 [PubMed] Free Access to Full Article Related Publications
PURPOSE OF REVIEW: The CARMA1/BCL10/MALT1 (CBM) complex is a multimeric signaling complex controlling several important aspects of lymphocyte activation. Gain-of-function mutations in the genes encoding CBM proteins or their upstream regulators are associated with lymphoid malignancies, whereas loss-of-function mutations lead to immunodeficiency. This review reports on recent findings advancing our understanding of how CBM proteins contribute to malignant and nonmalignant hematological diseases in humans.
RECENT FINDINGS: Somatic gain-of-function mutations of CARMA1 (also known as CARD11), originally described for patients with diffuse large B-cell lymphoma, have recently been identified in patients with acute T-cell leukemia/lymphoma or Sézary syndrome, and in patients with a B-cell lymphoproliferative disorder known as BENTA. Loss-of-function mutations of CARMA1 and MALT1, on the other hand, have been reported to underlie human immunodeficiency. Lately, it has become clear that CBM-dependent signaling promotes lymphomagenesis not only via NF-κB activation, but also via the AP-1 family of transcription factors. The identification of new substrates of the protease MALT1 and the characterization of mice expressing catalytically inactive MALT1 have deepened our understanding of how the CBM complex controls lymphocyte proliferation through promoting MALT1's protease activity.
SUMMARY: The discovery of CARMA1 gain-of-function mutations in T-cell malignancies and BENTA patients, as well as the association of CARMA1 and MALT1 mutations with human immunodeficiency highlight the importance of CBM proteins in the regulation of lymphocyte functions, and suggest that the protease activity of MALT1 might be targeted to treat specific lymphoid malignancies.

Yang Y, Kelly P, Shaffer AL, et al.
Targeting Non-proteolytic Protein Ubiquitination for the Treatment of Diffuse Large B Cell Lymphoma.
Cancer Cell. 2016; 29(4):494-507 [PubMed] Free Access to Full Article Related Publications
Chronic active B cell receptor (BCR) signaling, a hallmark of the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), engages the CARD11-MALT1-BCL10 (CBM) adapter complex to activate IκB kinase (IKK) and the classical NF-κB pathway. Here we show that the CBM complex includes the E3 ubiquitin ligases cIAP1 and cIAP2, which are essential mediators of BCR-dependent NF-κB activity in ABC DLBCL. cIAP1/2 attach K63-linked polyubiquitin chains on themselves and on BCL10, resulting in the recruitment of IKK and the linear ubiquitin chain ligase LUBAC, which is essential for IKK activation. SMAC mimetics target cIAP1/2 for destruction, and consequently suppress NF-κB and selectively kill BCR-dependent ABC DLBCL lines, supporting their clinical evaluation in patients with ABC DLBCL.

Chen CY, Chang JT, Ho YF, Shyu AB
MiR-26 down-regulates TNF-α/NF-κB signalling and IL-6 expression by silencing HMGA1 and MALT1.
Nucleic Acids Res. 2016; 44(8):3772-87 [PubMed] Free Access to Full Article Related Publications
MiR-26 has emerged as a key tumour suppressor in various cancers. Accumulating evidence supports that miR-26 regulates inflammation and tumourigenicity largely through down-regulating IL-6 production, but the underlying mechanism remains obscure. Here, combining a transcriptome-wide approach with manipulation of cellular miR-26 levels, we showed that instead of directly targeting IL-6 mRNA for gene silencing, miR-26 diminishes IL-6 transcription activated by TNF-α through silencing NF-κB signalling related factors HMGA1 and MALT1. We demonstrated that miR-26 extensively dampens the induction of many inflammation-related cytokine, chemokine and tissue-remodelling genes that are activated via NF-κB signalling pathway. Knocking down both HMGA1 and MALT1 by RNAi had a silencing effect on NF-κB-responsive genes similar to that caused by miR-26. Moreover, we discovered that poor patient prognosis in human lung adenocarcinoma is associated with low miR-26 and high HMGA1 or MALT1 levels and not with levels of any of them individually. These new findings not only unravel a novel mechanism by which miR-26 dampens IL-6 production transcriptionally but also demonstrate a direct role of miR-26 in down-regulating NF-κB signalling pathway, thereby revealing a more critical and broader role of miR-26 in inflammation and cancer than previously realized.

Demeyer A, Staal J, Beyaert R
Targeting MALT1 Proteolytic Activity in Immunity, Inflammation and Disease: Good or Bad?
Trends Mol Med. 2016; 22(2):135-150 [PubMed] Related Publications
MALT1 is a signaling protein that plays a key role in immunity, inflammation, and lymphoid malignancies. For a long time MALT1 was believed to function as a scaffold protein, providing an assembly platform for other signaling proteins. This view changed dramatically when MALT1 was also found to have proteolytic activity and a capacity to fine-tune immune responses. Preclinical studies have fostered the belief that MALT1 is a promising therapeutic target in autoimmunity and B cell lymphomas. However, recent studies have shown that mice expressing catalytically-inactive MALT1 develop multi-organ inflammation and autoimmunity, and thus have tempered this initial enthusiasm. We discuss recent findings, highlighting the urgent need for a better mechanistic and functional understanding of MALT1 in host defense and disease.

Bognar MK, Vincendeau M, Erdmann T, et al.
Oncogenic CARMA1 couples NF-κB and β-catenin signaling in diffuse large B-cell lymphomas.
Oncogene. 2016; 35(32):4269-81 [PubMed] Free Access to Full Article Related Publications
Constitutive activation of the antiapoptotic nuclear factor-κB (NF-κB) signaling pathway is a hallmark of the activated B-cell-like (ABC) subtype of diffuse large B-cell lymphomas (DLBCL). Recurrent oncogenic mutations are found in the scaffold protein CARMA1 (CARD11) that connects B-cell receptor (BCR) signaling to the canonical NF-κB pathway. We asked how far additional downstream processes are activated and contribute to the oncogenic potential of DLBCL-derived CARMA1 mutants. To this end, we expressed oncogenic CARMA1 in the NF-κB negative DLBCL lymphoma cell line BJAB. By a proteomic approach we identified recruitment of β-catenin and its destruction complex consisting of APC, AXIN1, CK1α and GSK3β to oncogenic CARMA1. Recruitment of the β-catenin destruction complex was independent of CARMA1-BCL10-MALT1 complex formation or constitutive NF-κB activation and promoted the stabilization of β-catenin. The β-catenin destruction complex was also recruited to CARMA1 in ABC DLBCL cell lines, which coincided with elevated β-catenin expression. In line, β-catenin was frequently detected in non-GCB DLBCL biopsies that rely on chronic BCR signaling. Increased β-catenin amounts alone were not sufficient to induce classical WNT target gene signatures, but could augment TCF/LEF-dependent transcriptional activation in response to WNT signaling. In conjunction with NF-κB, β-catenin enhanced expression of immunosuppressive interleukin-10 and suppressed antitumoral CCL3, indicating that β-catenin can induce a favorable tumor microenvironment. Thus, parallel activation of NF-κB and β-catenin signaling by gain-of-function mutations in CARMA1 augments WNT stimulation and is required for regulating the expression of distinct NF-κB target genes to trigger cell-intrinsic and extrinsic processes that promote DLBCL lymphomagenesis.

Ziółko E, Kokot T, Skubis A, et al.
The profile of melatonin receptors gene expression and genes associated with their activity in colorectal cancer: a preliminary report.
J Biol Regul Homeost Agents. 2015 Oct-Dec; 29(4):823-8 [PubMed] Related Publications
The antiproliferative and immunomodulatory effects of melatonin (MLT) have been demonstrated in a variety of neoplasms including colorectal cancer (CRC). In humans and other mammals, MLT acts on target tissues through membrane and retinoid nuclear receptors. The aim of this study was to evaluate transcription activity of melatonin receptors and genes associated with regulation of their activity in colorectal adenocarcinoma tissues in relation to clinical stage of cancer. A total of 24 pairs of surgically removed tumoral and healthy (marginal) tissue samples from colorectal cancer patients at clinical stages I-II and III-IV were collected. As an additional control, twenty normal samples were tak¬en from people whose large intestine tissues were reported as non-tumoral after colonoscopy. Expression of mRNA genes was studied by microarray HG-U133A analysis. The analysis of gene expression profile was performed using commercially available oligonucleotide microarrays of HG-U133A. High increase of MT1 mRNA expression levels in all cancerous samples vs non-cancerous tissues was observed. The MT2 mRNA expression levels increased slightly in marginal and malignant samples. Among the genes participating in the cascade of signal transfer in cells activated by MLT via melatonin receptors, we found encoding genes (GNA11, OXTR, TPH1) only for differentiating stage III - IV of CRC. Monitoring the expression levels of genes that are related to melatonin receptors may offer a strategy to anticipate tumour development and estimate the molecular changes that occur during carcinogenesis. The mechanism behind this association needs further elucidation.

Knies N, Alankus B, Weilemann A, et al.
Lymphomagenic CARD11/BCL10/MALT1 signaling drives malignant B-cell proliferation via cooperative NF-κB and JNK activation.
Proc Natl Acad Sci U S A. 2015; 112(52):E7230-8 [PubMed] Free Access to Full Article Related Publications
The aggressive activated B cell-like subtype of diffuse large B-cell lymphoma is characterized by aberrant B-cell receptor (BCR) signaling and constitutive nuclear factor kappa-B (NF-κB) activation, which is required for tumor cell survival. BCR-induced NF-κB activation requires caspase recruitment domain-containing protein 11 (CARD11), and CARD11 gain-of-function mutations are recurrently detected in human diffuse large B-cell lymphoma (DLBCL). To investigate the consequences of dysregulated CARD11 signaling in vivo, we generated mice that conditionally express the human DLBCL-derived CARD11(L225LI) mutant. Surprisingly, CARD11(L225LI) was sufficient to trigger aggressive B-cell lymphoproliferation, leading to early postnatal lethality. CARD11(L225LI) constitutively associated with B-cell CLL/lymphoma 10 (BCL10) and mucosa-associated lymphoid tissue lymphoma translocation gene 1 (MALT1) to simultaneously activate the NF-κB and c-Jun N-terminal kinase (JNK) signaling cascades. Genetic deficiencies of either BCL10 or MALT1 completely rescued the phenotype, and pharmacological inhibition of JNK was, similar to NF-κB blockage, toxic to autonomously proliferating CARD11(L225LI)-expressing B cells. Moreover, constitutive JNK activity was observed in primary human activated B cell-like (ABC)-DLBCL specimens, and human ABC-DLBCL cells were also sensitive to JNK inhibitors. Thus, our results demonstrate that enforced activation of CARD11/BCL10/MALT1 signaling is sufficient to drive transformed B-cell expansion in vivo and identify the JNK pathway as a therapeutic target for ABC-DLBCL.

Zhang Y, Wei Z, Li J, Liu P
Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue--from (auto)antigen driven selection to the activation of NF-κB signaling.
Sci China Life Sci. 2015; 58(12):1246-55 [PubMed] Related Publications
Lymphomas of mucosa-associated lymphoid tissue (MALT) are typically present at sites such as the stomach, lung or urinary tract, where lymphoid tissues scatter in mucosa lamina propria, intra- or sub-epithelial cells. The infection of certain pathogens, such as Helicobacter pylori, Chlamydophila psittaci, Borrelia burgdorferi, hepatitis C virus, or certain autoantigens cause these sites to generate a germinal center called the "acquired lymphoid tissue". The molecular pathogenesis of MALT lymphoma is a multi-step process. Receptor signaling, such as the contact stimulation of B cell receptors and CD4 positive T cells mediated by CD40/CD40-ligand and T helper cell type 2 cytokines like interleukin-4, contributes to tumor cell proliferation. A number of genetic alterations have been identified in MALT lymphoma, and among them are important translocations, such as t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32). Fusion proteins generated by these translocations share the same NF-κB signaling pathway, which is activated by the caspase activation and recruitment domain containing molecules of the membrane associated guanylate kinase family, B cell lymphoma-10 and MALT1 (CBM) protein complex. They act downstream of cell surface receptors, such as B cell receptors, T cell receptors, B cell activating factors and Toll-like receptors, and participate in the biological process of MALT lymphoma. The discovery of therapeutic drugs that exclusively inhibit the antigen receptor signaling pathway will be beneficial for the treatment of B cell lymphomas in the future.

Choung H, Kim YA, Kim N, et al.
Clinicopathologic Study of Chromosomal Aberrations in Ocular Adnexal Lymphomas of Korean Patients.
Korean J Ophthalmol. 2015; 29(5):285-93 [PubMed] Free Access to Full Article Related Publications
PURPOSE: The incidence and clinical correlation of MALT1 translocation and chromosomal numerical aberrations in Korean patients with ocular adnexal mucosa associated lymphoid tissue (MALT) lymphoma have not yet been reported. We investigated the incidence and clinicopathologic relationship of these chromosomal aberrations in ocular adnexal MALT lymphomas in a Korean population.
METHODS: Thirty ocular adnexal MALT lymphomas were investigated for the t(11;18) API2-MALT1, t(14;18) IgH-MALT1 translocations and chromosomes 3 and 18 aneuploidies using fluorescence in situ hybridization. Patient medical records were reviewed retrospectively for information on demographics and clinical characteristics, including treatment response.
RESULTS: The MALT1 gene rearrangement was found in one out of 30 cases. The t(14;18) IgH-MALT1 translocation was demonstrated in only one case (3.3%), and the t(11;18) API2-MALT1 translocation was not found in any of the cases. Trisomy 3 was observed in three ocular adnexal MALT lymphomas (10.0%), and five cases showed trisomy 18 (16.7%). Translocation positive cases also showed trisomy 18. One case of tumor relapse showed trisomy 18 only in the recurrent biopsies. There were no statistically significant correlations between chromosomal aberrations and clinical characteristics and treatment responses.
CONCLUSIONS: Translocations involving the MALT1 gene are not common in Korean ocular adnexal MALT lymphomas. The t(14;18) translocation was detected in only one out of 30 cases, and the t(11;18) translocation was not found at all. Furthermore, the chromosomal aberrations found in this study had no prognostic implications.

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