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Auto-Ubiquitination-Induced Degradation of MALT1-API2 Prevents BCL10 Destabilization in t(11;18)(q21;q21)-Positive MALT Lymphoma  [PDF]
Heidi Noels, Riet Somers, Hongxiang Liu, Hongtao Ye, Ming-Qing Du, Christiane De Wolf-Peeters, Peter Marynen, Mathijs Baens
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0004822
Abstract: Background The translocation t(11;18)(q21;q21) is the most frequent chromosomal aberration associated with MALT lymphoma and results in constitutive NF-κB activity via the expression of an API2-MALT1 fusion protein. The properties of the reciprocal MALT1-API2 were never investigated as it was reported to be rarely transcribed. Principal Findings Our data indicate the presence of MALT1-API2 transcripts in the majority of t(11;18)(q21;q21)-positive MALT lymphomas. Based on the breakpoints in the MALT1 and API2 gene, the MALT1-API2 protein contains the death domain and one or both immunoglobulin-like domains of MALT1 (~90% of cases) - mediating the possible interaction with BCL10 - fused to the RING domain of API2. Here we show that this RING domain enables MALT1-API2 to function as an E3 ubiquitin ligase for BCL10, inducing its ubiquitination and proteasomal degradation in vitro. Expression of MALT1-API2 transcripts in t(11;18)(q21;q21)-positive MALT lymphomas was however not associated with a reduction of BCL10 protein levels. Conclusion As we observed MALT1-API2 to be an efficient target of its own E3 ubiquitin ligase activity, our data suggest that this inherent instability of MALT1-API2 prevents its accumulation and renders a potential effect on MALT lymphoma development via destabilization of BCL10 unlikely.
Immunohistochemical comparison of CD5, lambda, and kappa expression in primary and recurrent buccal Mucosa-associated lymphoid tissue (MALT) lymphomas
Toshiaki Tanaka, Kenichirou Kitabatake, Mituyoshi Iino, Kaoru Goto
Diagnostic Pathology , 2011, DOI: 10.1186/1746-1596-6-82
Abstract: Primary MALT lymphomas can also occur in the oral cavity, although their appearance in this location is rare. The neoplastic cells of which MALT lymphomas are composed express B-cell antigens and show monotypic immunoglobulin expression with light-chain restriction.Although neoplastic MALT lymphoma cells do not express CD5, previous studies have shown that CD5 positive MALT lymphomas are more prone to dissemination than those that do not express CD5. Moreover, there are some reports that describe kappa- and lambda- dual light chain expression in B cell malignant neoplasms.A 66-year-old Japanese woman with swelling of the right buccal mucosa was referred to our hospital. The lesion was excised and was pathologically diagnosed as a MALT lymphoma tumor with a t(11;18)(q21;q21) chromosome translocation.Swelling of the right buccal mucosa recurred 2 years later. The recurrent tumor was then excised and pathologically diagnosed as MALT lymphoma.Immunohistochemical examination of CD5, lambda, and kappa expressions revealed that the primary tumor was positive for CD5, kappa, and lambda, but the recurrent tumor was weakly positive for CD5 and kappa.With respect to lambda positivity, the recurrent tumor showed negativity.Our study suggests that immunohistochemical expression of CD5, kappa, and lambda in oral MALT lymphoma have the risk of recurrence.We first described the recurrence of CD5 positive MALT lymphoma in the oral cavity and compared the immunohistochemical expressions of CD5, lambda, and kappa between the primary and recurrent tumors.Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of extranodal marginal zone B-cell lymphoma and is a distinct subtype of non-Hodgkin's lymphoma [1].The most common site of MALT lymphomas is the stomach, and the majority of gastric MALT lymphomas are associated with Helicobacter pylori infection [2]. Other sites where MALT lymphomas can occur include the orbit, lung, salivary glands, thyroid, skin, intestine, and liver [3].
Gastric mucosa-associated lymphoid tissue lymphomas and Helicobacter pylori infection: A Colombian perspective  [cached]
Sally Yepes,Maria Mercedes Torres,Carlos Saavedra,Rafael Andrade
World Journal of Gastroenterology , 2012, DOI: 10.3748/wjg.v18.i7.685
Abstract: AIM: To assess the significance of chromosome translocation t(11;18)(q21;q21), B-cell lymphoma 10 (BCL-10) protein and Helicobacter pylori (H. pylori) infection in gastric mucosa-associated lymphoid tissue (MALT) lymphoma in Colombia. METHODS: Fifty cases of gastric MALT lymphoma and their respective post-treatment follow-up biopsies were examined to assess the presence of the translocation t(11;18)(q21;q21) as identified by fluorescence in situ hybridization; to detect protein expression patterns of BCL10 using immunohistochemistry; and for evaluation of tumor histology to determine the correlation of these factors and resistance to H. pylori eradication. RESULTS: Infection with H. pylori was confirmed in all cases of gastric MALT lymphoma in association with chronic gastritis. Bacterial eradication led to tumor regression in 66% of cases. The translocation t(11;18)(q21;q21) was not present in any of these cases, nor was there evidence of tumor transformation to diffuse large B-cell lymphoma. Thirty-four percent of the patients showed resistance to tumor regression, and within this group, 7 cases, representing 14% of all those analyzed, were considered to be t(11;18)(q21;q21)-positive gastric MALT lymphomas. Protein expression of BCL10 in the nucleus was associated with the presence of translocation and treatment resistance. Cases that were considered unresponsive to therapy were histologically characterized by the presence of homogeneous tumor cells and a lack of plasmacytic differentiation. Responder cases exhibited higher cellular heterogeneity and a greater frequency of plasma cells. CONCLUSION: Both t(11;18)(q21;q21)-positive MALT lymphoma cases and those with nuclear BCL10 expression are considered resistant to H. pylori eradication. It is suggested that chronic antigenic stimulation is not a dominant event in resistant cases.
Running in the family: MALT lymphoma and autoimmune disease in mother and daughter  [cached]
Barbara Kiesewetter,Marlene Troch,Leonhard Müllauer,Markus Raderer
World Journal of Gastrointestinal Oncology , 2012, DOI: 10.4251/wjgo.v4.i2.26
Abstract: Gastric B-cell lymphoma of the mucosa associated lymphoid tissue (MALT) lymphoma is one of the most common forms of extranodal lymphoma. In addition to infection with Helicobacter pylori (H. pylori), the presence of an underlying autoimmune disease has also been associated with MALT lymphoma development. To date, no familial predisposition for MALT lymphomas has been reported as opposed to other types of lymphoma. A 65-year-old woman was admitted at our institution in 1998 with a diagnosis of H. pylori positive gastric MALT lymphoma and the presence of chronic autoimmune thyroiditis was established on further work-up. H. pylori eradication did not result in regression of the lymphoma and RT-PCR showed the presence of the t(11;18)(q21;q21) translocation. About 1.5 years after H. pylori eradication, chemotherapy with cladribine resulted in complete remission. Due to lymphoma recurrence 13 mo later, radiotherapy to the stomach (46 Gy) resulted in minimal residual disease without further progression. The patient developed a second malignancy (Epstein-Bar virus-associated anaplastic large cell lymphoma in the mediastinum) in 2004 which initially responded to two courses of chemotherapy, but she refused further therapy and died of progressive lymphoma in 2006. In 2008, her 55 years old daughter with a long standing Sj gren’s syndrome was diagnosed with MALT lymphoma of the right parotid, but no evidence of gastric involvement or H. pylori infection was found. Currently, she is alive without therapy and undergoing regular check-ups. To our knowledge, this is the first report of MALT lymphoma in a first-degree relative of a patient with gastric MALT lymphoma in the context of two autoimmune diseases without a clearly established familial background.
Primary MALT lymphomas of the stomach: A pathological study of 18 cases
Venizelos,I.; Tamiolakis,D.; Lambropoulou,M.; Bolioti,S.; Nikolaidou,S.; Alexiadis,G.; Papadopoulos,N.;
Revista Espa?ola de Enfermedades Digestivas , 2007, DOI: 10.4321/S1130-01082007000500005
Abstract: aim: it is doubtful that whoever is suffering from gastric malt lymphoma will escape from the disease, if treated with medication against helicobacter pylori. material and methods: a cohort of 18 patients was analysed. ten hosts had primary gastric malt lymphoma and were treated with gastric resection as the initial therapy. eight hosts received antibiotics against helicobacter pylori as the initial treatment. in all 18 patients helicobacter pylori status, endoscopic findings and pathology features were evaluated. immunohistochemistry was performed to assess the bcl-2 and p53 status. results: patients with low grade malt lymphoma: a) were helicobacter pylori positive (5 of 5); b) had a superficial lesion (5 of 5); c) had no lymph node involvement (5 of 5); and d) were downstaged by comparison to patients with high grade tumor. bcl-2 was positive in 4 of 5 low grade tumors, and p53 was positive in 12 of 13 high grade ones. investigation of patients with 5-year follow up (n = 18) revealed that all but one low-grade tumors remained superficial with no progression. these tumors were bcl-2+/p53-, and the one with a bcl-2+/p53+ immunophenotype progressed to an ulcerated low-grade tumor after disappearance of helicobacter pylori. complete regression was found in 6 of 8 patients from the non surgically treated group (n = 8) after helicobacter pylori eradication. these tumors were superficial/low grade/node negative/bcl-2+/p53 inconclusive (n = 2), superficial/low grade/node negative/bcl-2+/p53- (n = 2), and ulcerative/high grade/node negative/bcl-2+/p53- (n = 2). the two persistent tumors were ulcerative/high grade/node negative/bcl-2+/p53+. conclusion: gastric malt lymphoma helicobacter pylori+/superficial/low grade/bcl-2+/p53- will disappear after helicobacter pylori eradication.
Primary MALT Type Skin Lymphoma—Is ‘Wait and See’ a Possible Strategy?
Florentina Silvia Delli,Thomas Zaraboukas,Ioanna Mandekou-Lefaki
Clinical Medicine : Oncology , 2008,
Abstract: Primary cutaneous lymphomas are the second most common site of extranodal non-Hodgkin lymphoma. A specifically type named extranodal marginal zone B-cell lymphomas are indolent low-grade neoplasma. We report a case of a 42-year-old white man with multiple subcutaneous tumors located on the trunk and neck. The histopathological exam showed a non-epidermotropic, dense lymphocytic infiltrate. Histologic, immunohistochemical and cytologenetic analysis diagnosed primary cutaneous B-cell lymphoma MALT type. Investigation for other extranodal MALT lymphoma gastrointestinal tract, lung, salivary and thyroid glands was negative. The patient refused radiotherapy, but he accepted every 6 months close follow-up. Over a seven years period, we noticed a progressively disappearance of the skin lesions. The necessity of aggressive treatment of this disease with excellent prognosis is discussed. The treatment necessity of primary cutaneous B-cell lymphoma MALT type is discussed.
Monoubiquitination and Activity of the Paracaspase MALT1 Requires Glutamate 549 in the Dimerization Interface  [PDF]
Katrin Cabalzar, Christiane Pelzer, Annette Wolf, Georg Lenz, Justyna Iwaszkiewicz, Vincent Zoete, Stephan Hailfinger, Margot Thome
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0072051
Abstract: The mucosa-associated lymphoid tissue protein-1 (MALT1, also known as paracaspase) is a protease whose activity is essential for the activation of lymphocytes and the growth of cells derived from human diffuse large B-cell lymphomas of the activated B-cell subtype (ABC DLBCL). Crystallographic approaches have shown that MALT1 can form dimers via its protease domain, but why dimerization is relevant for the biological activity of MALT1 remains largely unknown. Using a molecular modeling approach, we predicted Glu 549 (E549) to be localized within the MALT1 dimer interface and thus potentially relevant. Experimental mutation of this residue into alanine (E549A) led to a complete impairment of MALT1 proteolytic activity. This correlated with an impaired capacity of the mutant to form dimers of the protease domain in vitro, and a reduced capacity to promote NF-κB activation and transcription of the growth-promoting cytokine interleukin-2 in antigen receptor-stimulated lymphocytes. Moreover, this mutant could not rescue the growth of ABC DLBCL cell lines upon MALT1 silencing. Interestingly, the MALT1 mutant E549A was unable to undergo monoubiquitination, which we identified previously as a critical step in MALT1 activation. Collectively, these findings suggest a model in which E549 at the dimerization interface is required for the formation of the enzymatically active, monoubiquitinated form of MALT1.
Nódulos pulmonares fluctuantes como forma de presentación de un linfoma MALT
Dolz Aspas,R.; Toyas Miazza,C.; Ruiz Ruiz,F.; Morales Rull,J. L.; Pérez Calvo,J. I.;
Anales de Medicina Interna , 2003, DOI: 10.4321/S0212-71992003001100007
Abstract: mucosa associated lymphoid tissue (malt) lymphomas are a group of non- hodgkin?s lymphomas of low malignancy degree. the most frequent location is the gastrointestinal tract. its primary pulmonary presentation is unusual and heterogeneous from point of view radiological. woman 61 years old with antecedents of vitiligo, gastric ulcus, cirrhosis by vhc, that go into the hospital by sudden disnea, thoracic paint with pleural characterises and fever of 38.5o c, her thorax radiography and thoracic tac showed nodes that affect to different pulmonary lobes. the cytology by paaf confirms their malignant nature. in subsequent radiological controls it was notice the nodels took away completely and returns in different pulmonary place in each recurrence. the presentation like fluctuant pulmonary nodes is exceptional in a malt lymphoma. it was described a higher incidence of vhc infection and tumour. the evidence of chronic hepatitis by virus c disease, and local chronic inflammatory process as well as autoimmune disorders may be considerate like a factor that contribute to malt lymphoma.
Gastrointestinal lymphomas in a North American population: clinicopathologic features from one major Central-Midwestern United States tertiary care medical center
Joshua Warrick, Jingqin Luo, Diane Robirds, Julie Branson, John L Frater, Friederike Kreisel, Anjum Hassan, TuDung T Nguyen
Diagnostic Pathology , 2012, DOI: 10.1186/1746-1596-7-76
Abstract: We retrospectively evaluated the clinical, molecular and histologic features of North American primary and secondary GI lymphomas diagnosed from 2000–2009 seen at our institution. We utilized immunohistochemistry and fluorescence in situ hybridization to further evaluate a subset of the gastric lymphomas.Extranodal marginal zone lymphomas of mucosal associated lymphoid tissue (MALTs) and diffuse large B cell lymphomas (DLBCLs) were the most common subtypes of GI lymphomas. Select gastric DLBCLs (N?=?6) and MALTs (N?=?13) were further examined for API2-MALT1 and IGH translocations, and P16 and P53 protein expression. Gastric MALTs showed frequent API2-MALT1 (38%) but not IGH translocations (0%), and the DLBCLs showed neither translocation. Expression of P16 and P53 proteins and the proliferative index were compared between high grade gastric lymphomas (gastric DLBCLs) and low grade gastric lymphomas (gastric MALTs). P53 overexpression (P?=?0.008) and a high proliferation index [Ki-67] (P?=?0.00042) were significantly associated with gastric DLBCL, but no statistically significant difference was observed in P16 expression (p?=?0.108) between gastric DLBCL and gastric MALT.Our study revealed that GI lymphomas from a Central-Midwestern North American population showed differences and similarities to non-North American cohorts. In addition, API2-MALT1, P16 and P53 abnormalities occurred frequently in gastric lymphomas from this North American population.The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1415505838687793 webciteGastrointestinal (GI) lymphomas are a relatively common type of extranodal lymphoma, accounting for up to 30-50% of extranodal lymphomas in some series [1,2]. However, the majority of population based studies have been performed on Asian or European cohorts [2-9] with only one recent study from a Canadian-North American cohort [10]. Though studies from the United States (US) have been performed, mos
The clinical significance of CD97, NF-kB and COX-2 ingastric MALT lymphomas  [PDF]
Shao-Liang Han, Jun Cheng, Xiu-Ling Wu, Zeng-Rong Jia, Peng-Fei Wang, Zhan-Wei Wang
Journal of Biomedical Science and Engineering (JBiSE) , 2011, DOI: 10.4236/jbise.2011.47061
Abstract: Background and Objectives: Increased expression of the CD97, nuclear factor-kB (NF-kB) and cyclooxygenase-2 (COX-2) has been found to play an important role in development of many cancers, including gastric neoplasm. However, the expression and biological behavior of CD97, NF-kB and COX-2 in gastric MALT (mucosa-associated lymphoid tissue) lymphoma has not been well investigated. Methods: The expressions of CD97, COX-2 and NF-kB in 47 cases of gastric MALT lymphoma were detected immunohistochemically, and the relevance between their expressions and the biological behavior was analyzed retrospectively. Results: 1) The expressions of CD97, NF-kB and COX-2 were 87.2%, 36.2% and 48.9%, respectively; 2) The difference of CD97 expression between depth of invasion limited in mucosa and submucosa and beyond muscularis propria was significant (100.0% vs. 71.4%, P < 0.01). Moreover, the expression of nuclear CD97 between stage IIE, III, IV and stage I patients showed significant difference (96.4% vs. 73.7%, P < 0.05); 3) The expression of NF-kB was significantly correlated with tumor size, depth of invasion and stage; 4) The expression of COX-2 was significantly correlated with Helicobacter pylori infection, clinical stage, depth of invasion and tumor size (P < 0.05). Conclusions: Expressions of CD97, NF-κB and COX-2 were correlated with tumor invasion and metastasis in gastric MALT lymphoma.
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