Pathogenesis Of Mucosa-associated Lymphoid Tissue Lymphoma Research Articles

Clinicopathological features and possible prognostic factors in parotid lymphomas

To investigate the clinicopathological features and prognostic factors in lymphoma of parotid origin. Clinicopathological data of the patients with parotid lymphoma who were initially diagnosed in Peking University Hospital of Stomatology from 2006 to 2016 were collected and analyzed retrospectively. The patients were followed-up for 5 to 149 months with a median period of 45 months, and the factors influencing the prognosis were evaluated. A total of 41 patients with primary parotid lymphoma were included in this retrospective study. The rate of male to female was 1:2.15. The median age was 57 years (ranging from 8 months to 91 years). According to WHO classification, 40 cases (97.1%) were diagnosed as non-Hodgkin lymphoma (NHL), including 15 cases of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), 14 cases of diffuse large B cell lymphoma (DLBCL) as well as 4 cases of follicular lymphoma, while other subtypes of NHL were rare. Only one case was diagnosed as Hodgkin lymphoma. Regarding the clinical staging at the initial diagnosis, 37 patients (90.2%) were diagnosed as stage IE or IIE of the disease, while 4 patients (9.8%) as stage IIIE or stage IVE. Seven patients (17.1%) had a history of Sjögren syndrome (SS), all of whom were MALT lymphoma. The mean ill duration of the 41 patients were 20.7 months. Thirty-two patients (78%) presented a slowly growing painless mass in the parotid gland. Treatment options included localized therapy and systemic therapy, all of whom had good curative effect. Nine patients (21.9%) died during the follow-up period. The overall survival rates of 2-year and 5-year were 84.5% and 81.3% respectively. The univariate analysis demonstrated statistically significant differences for accelerated growth of tumor (P=0.005), and presence of tumor capsule (P=0.011). The multi-univariate analysis demonstrated statistically significant differences for presence of tumor capsule (P=0.041). A large majority of primary parotid lymphoma were NHL, among which MALT lymphoma and DLBCL were common subtypes. Most patients presented an indolent mass in parotid gland, which should be distinguished from the parotid benign tumors. SS is closely related to the pathogenesis of MALT lymphoma. The prognosis is better than that of other malignant parotid tumors. Absence of tumor capsule may predict a poor prognosis in patients with parotid lymphoma.

The role of miRNAs and epigenetic mechanisms in primary gastric mucosa-associated lymphoid tissue lymphoma.

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is a rare low-grade B-cell non-Hodgkin lymphoma associated with Helicobacter pylori infection and the subsequent chronic inflammation. Significant progress in understanding the pathogenesis of the disease has already been made. However, the exact molecular pathways of lymphomagenesis remain unclear. Furthermore, difficulties regarding accurate diagnosis of gastric MALT lymphoma and its discrimination from gastritis or other lymphoma subtypes arise. Recent studies evaluate the role of miRNAs and epigenetic alterations on MALT lymphoma pathogenesis and prognosis. This review critically summarizes the most important data on the role of miRNAs and epigenetics in MALT lymphomas pathogenesis, prognosis and treatment.

Low Protein A20 in Minor Salivary Glands is Associated with Lymphoma in Primary Sjögren's Syndrome.

Patients with primary Sjögren's syndrome (pSS) have an increased risk of developing lymphomas, particularly the subtype mucosa-associated lymphoid tissue (MALT) lymphoma. Chronic antigen stimulation and increased activation of nuclear factor-κB (NF-κB) are important factors for the pathogenesis of MALT lymphomas. Protein A20 is an inhibitor of NF-κB. A recent study of pSS-associated MALT lymphomas identified potential functional abnormalities in the TNFAIP3 gene, which encodes protein A20. The present study aimed to assess protein A20 by immunohistochemistry (IHC) in minor salivary glands (MSGs) and lymphoma tissue sections of patients with pSS and investigate a potential association with lymphoma development. Protein A20 staining in lymphocytes was scored in four categories (0=negative, 1=weak, 2=moderate and 3=strong). For statistical purposes, these scores were simplified into negative (scores 0-1) and positive (scores 2-3). We investigated associations between protein A20-staining, focus scores, germinal centre (GC)-like structures and monoclonal B-cell infiltration in MSGs. MSG protein A20 staining was weaker in pSS patients with lymphomas than in those without lymphomas (P=0.01). Weak protein A20 staining was also highly associated with a lack of GC formation (P<0.01). Finally, weaker A20 staining was observed in the majority of pSS-associated MALT lymphoma tissues. In conclusion, we found absent or weak protein A20 immunoreactivity in MSGs of patients with pSS with lymphomas. This finding indicates that protein A20 downregulation in lymphocytes might be a mechanism underlying lymphoma genesis in patients with pSS.

Molecular pathogenesis of lymphomas of mucosa-associated lymphoid tissue--from (auto)antigen driven selection to the activation of NF-κB signaling.

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.

Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2-MALT1 in MALT lymphoma.

MALT1 is the only known paracaspase and is a critical mediator of B- and T-cell receptor signalling. The function of the MALT1 gene is subverted by oncogenic chimeric fusions arising from the recurrent t(11;18)(q21;q21) aberration, which is the most frequent translocation in mucosa-associated lymphoid tissue (MALT) lymphoma. API2-MALT1-positive MALT lymphomas manifest antibiotic resistance and aggressive clinical behaviour with poor clinical outcome. However, the mechanisms underlying API2-MALT1-induced MALT lymphomagenesis are not fully understood. Here we show that API2-MALT1 induces paracaspase-mediated cleavage of the tumour suppressor protein LIMA1. LIMA1 binding by API2-MALT1 is API2 dependent and proteolytic cleavage is dependent on MALT1 paracaspase activity. Intriguingly, API2-MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo. Importantly, primary MALT lymphomas harbouring the API2-MALT1 fusion uniquely demonstrate LIMA1 cleavage fragments. Our studies reveal a novel paracaspase-mediated oncogenic gain-of-function mechanism in the pathogenesis of MALT lymphoma.

Molecular Pathogenesis of MALT Lymphoma.

Approximately 8% of all non-Hodgkin lymphomas are extranodal marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT), also known as MALT lymphoma, which was first described in 1983 by Isaacson and Wright. MALT lymphomas arise at a wide range of different extranodal sites, with the highest frequency in the stomach, followed by lung, ocular adnexa, and thyroid, and with a low percentage in the small intestine. Interestingly, at least 3 different, apparently site-specific, chromosomal translocations and missense and frameshift mutations, all pathway-related genes affecting the NF-κB signal, have been implicated in the development and progression of MALT lymphoma. However, these genetic abnormalities alone are not sufficient for malignant transformation. There is now increasing evidence suggesting that the oncogenic product of translocation cooperates with immunological stimulation in oncogenesis, that is, the association with chronic bacterial infection or autoaggressive process. This review mainly discusses MALT lymphomas in terms of their genetic aberration and association with chronic infections and summarizes recent advances in their molecular pathogenesis.

Breast MALT lymphomas: A clinicopathological and cytogenetic study of 9 cases

Primary breast mucosa-associated lymphoid tissue (MALT) lymphomas are uncommon and restricted diagnostic criteria should be used to exclude breast involvement by systemic lymphomas. The molecular pathogenesis of primary breast MALT lymphomas is not clear because of the rarity of the disease. Generally the molecular studies of MALT lymphoma in extranodal sites have shown the presence of different chromosomal aberrations, mutually exclusive with substantial differences in their frequency relatively to topographic localization. Few cases of breast MALT lymphomas in the literature have been assessed for MALT lymphoma-associated translocations and BCL10 expression, underlying their rarity in primary breast MALT lymphomas. In our study, we analyzed a series of nine cases of primary breast MALT lymphomas. FISH results showed evidence of MALT1 gene rearrangements in four primary breast lymphomas, in particular three cases with t(11;18)(q21;q21) and one case with t(14;18)(q32;q21). In addition, BCL10 gene rearrangement was not observed. There was no evidence of BCL10 gene translocation in any of the neoplasms assessed. Our data indicate that MALT1 gene rearrangements are not rare in primary breast MALT lymphoma in contrast with results of previous series. Finally, t(11;18) has been observed to be significantly associated with high intensity cytoplasmic BCL10 expression underlying cross-talk between MALT1 and BCL10 pathways in the pathogenesis of MALT lymphomas.

Two Cases of Gastric MALT Lymphoma Diagnosed at Long Last after Successful Eradication ofHelicobacter pylori

The gastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a rare disease. Helicobacter pylori infection is known as an important etiologic factor of the pathogenesis of MALT lymphoma. H. pylori colonization at the epithelium of gastric mucosa induces T cell and B cell recruitment. T cell induced B cell proliferation develops the MALT in the gastric mucosa. Monoclonal proliferation of B cell in the MALT transform into MALT lymphoma. The eradication of H. pylori is known to induce remission of the disease in more than 80% of patients. But there is no report on progression and development of MALT lymphoma after H. pylori eradication. We experienced two cases of gastric B cell MALT lymphoma diagnosed at long last, after the successful eradication of H. pylori. (Korean J Helicobacter Up Gastrointest Res 2012;12:265-270)

Pathogenesis of Gastric MALT Lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphoma is a heterogeneous form of a B-cell non-Hodgkin’s lymphoma with extranodal location.In the view of molecular biology, there are two types of MALT lymphoma: translocationnegative MALT lymphoma and translocation-positive MALT lymphoma. The pathogenesis of translocation-negative MALT lymphoma is driven by an active immune response to Helicobacter pylori infection. Thismost probably underscores the tumor cell survival and proliferation, and thus determines their response to Helicobacter pylorieradication. The oncogenic products of t(1;14) (p22;q32)/CL10-IGH, t(14;18)(q32;21)/IGH-MALT1 and t(11;18)(q21;q21)/API2MALT1, found in translocation-positive MALT lymphoma, are all potent activators of the NF-κB activation pathway. They activate the canonical NFκB activation pathway, and also potentially trigger directly and /r indirectly activation of the non-canonical NF-κB pathway. Inactivation of the global NFκB inhibitor A20 also impacts upon multiple signaling pathways leading to NF-κB activation and thus potentially exacerbates the effect of stimulation of surface receptors. This review discusses the recent advances in the molecular pathogenesis of MALT lymphoma, and explores how the above genetic abnormalities cooperate with immunological stimulation in the development of lymphoma. (Korean J Helicobacter Up Gastrointest Res 2011;11: 145-155)

Molecular Genetic Approach of Gastric MALT Lymphoma

Mucosa-associated lymphoid tissue (MALT) lymphoma is a common low grade B-cell lymphoma arising from a background of chronic inflammatory disease at a number of mucosal sites. The association between Helicobacter pylori and gastric MALT lymphoma is well known and it appears that H. pylori is critical for lymphomagenesis and also creates a microenvironment favoring the growth of neoplastic B cells. The understanding of MALT lymphoma biology has significantly improved, and at least 4 recurrent translocations t(11;18)/ API2-MALT1, t(1;14)/IGH-BCL10, t(14;18)/IGH-MALT1 and t(3;14)/IGH-FOXP1 have been implicated in the pathogenesis of MALT lymphoma. Here, we review the recent advances in association of microorganisms with MALT lymphoma and the molecular genetics underlying the lymphoma development. (Korean J Helicobacter Up Gastrointest Res 2011;11:161-164)

MALT lymphoma: many roads lead to nuclear factor-κb activation

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is characterized genetically by several recurrent, but mutually exclusive, chromosome translocations. To date, it has been shown that at least the oncogenic products of t(1;14)(p22;q32)/BCL10-IGH, t(14;18)(q32;21)/IGH-MALT1 and t(11;18)(q21;q21)/API2-MALT1 activate the nuclear factor (NF)-κB activation pathway. Recently, A20, an essential global NF-κB inhibitor, was found to be inactivated by somatic deletion and/or mutation in translocation-negative MALT lymphomas. However, these genetic abnormalities alone are not sufficient for malignant transformation and thus need to cooperate with other factors in MALT lymphomagenesis. Recent studies have shown steady, exciting progresses in our understanding of the biological functions of BCL10, MALT1 and A20 in the regulation of the NF-κB activation pathways and the biology of lymphocytes. This review discusses the implication of these recent advances in the molecular pathogenesis of MALT lymphoma, and explores how the above genetic abnormalities cooperate with immunological stimulation in the development of lymphoma.

Pleuric presentation of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue: a case report and a review of the literature

A primary pleural marginal zone B cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a very rare eventuality. Here, we report a rare case of MALT lymphoma arising in the pleura and update the literature on this topic. A 74-year-old female was hospitalized for persistent cough and weakness. A chest radiograph and total-body CT scan showed only large right-sided pleural effusion, and the coexistence of pleural thickening. Video-assisted thoracoscopic exploration and a talc pleurodesis were performed and microscopic and immunohistochemical findings showed that the tumor was a pleural MALT lymphoma. The patient received immunotherapy with Rituximab and obtained a good response that lasted 2 years. To the best of our knowledge, only seven cases of primary pleural MALT lymphoma have been documented until recently, mostly from Japan with a mean age for all patients of 60.5 years. The pathogenesis of MALT lymphomas remains unclear, although a possible chronic antigenic stimulation by microbial pathogens and/or autoantigens has been hypothesized. Surgical resection was performed in most cases, and some patients received postoperative chemotherapy or immunotherapy. The clinicopathologic characteristics and management of this extremely rare disease are also discussed.

Gastric MALT lymphoma: a model of chronic inflammation-induced tumor development

Mucosa-associated lymphoid tissue (MALT) lymphoma, or extranodal marginal zone lymphoma of MALT, is an indolent B-cell non-Hodgkin lymphoma arising in lymphoid infiltrates that are induced by chronic inflammation in extranodal sites. The stomach is the most commonly affected organ, in which MALT lymphoma pathogenesis is clearly associated with Helicobacter pylori gastroduodenitis. Gastric MALT lymphoma has attracted attention because of the involvement of genetic aberrations in the nuclear factor kappaB (NFkappaB) pathway, one of the most investigated pathways in the fields of immunology and oncology. This Review presents gastric MALT lymphoma as an outstanding example of the close pathogenetic link between chronic inflammation and tumor development, and describes how this information can be integrated into daily clinical practice. Gastric MALT lymphoma is considered one of the best models of how genetic events lead to oncogenesis, determine tumor biology, dictate clinical behavior and represent viable therapeutic targets. Moreover, in view of the association of gastric MALT lymphoma with dysregulation of the NFkappaB pathway, this signaling pathway will be discussed in depth in both normal and pathological conditions, highlighting strategies to identify new therapeutic targets in this lymphoma.

An Aggressive MALT Lymphoma Despite Negative Helicobacter pylori Testing

Purpose: MALT lymphoma is a form of non-Hodgkin B cell lymphoma (NHL) involving the mucosa-associated lymphoid tissue (MALT); however, the occurrence of Helicobacter pylori-negative lymphoma of the stomach—a primary gastric lymphoma, is not very common. Methods: We report a case of a 49-year-old Hispanic female with complaints of intermittent gastric pain, nausea and occasional vomiting for 2 years. The patient stated her pain was dull and went away with food and admitted to weight loss. She denied any significant past medical history or any familial gastrointestinal issues. Her lab values were within normal limits, except for mild anemia. Her physical exam was notable for epigastric tenderness. Subsequently, the patient was scheduled for upper endoscopy which demonstrated superficial ulceration, limited distensibility and rigidity. Extensive biopsies of the antrum and proximal stomach revealed necrotic debris with acute leucocytic exudation and extranodal marginal zone B cell lymphoma. Giemsa staining and serology for H. pylori was negative. The patient was then empirically started on triple antibiotic therapy (Amox/clav/PPI) for H. pylori eradication, and scheduled for endoscopic ultrasound (EUS). The EUS demonstrated excellent 5 layer echopattern throughout the stomach. The MALT lymphoma appeared to be confined to the superficial antral mucosa without peri gastric lymph node involvement. The patient underwent repeat endoscopy with multiple biopsies 4 weeks later which showed histologic persistence of MALT lymphoma. She was therefore referred to an oncologist for systemic chemotherapy. Results: Presently, 12 clinical studies with almost 400 patients and case reports have shown that a cure of H. pylori infection is associated with complete remission in approximately 80% of patients with low-grade MALT lymphoma in an early clinical stage. However, what can be done if the patient is found to be H. pylori negative? Rates of about 7-15% of H. pylori-negative gastric MALT lymphoma patients have been reported. The reason for the occurrence of a maltoma without the evidence of H. pylori is unknown. Perhaps multiple etiological factors are at fault for the pathogenesis of MALT lymphoma. Conclusion: Eradication strategies may not entirely preclude the risk for neoplastic transformation. H. pylori negative associated MALT may indeed represent a different clinical entity with more aggressive characteristics. Though rates are low, they remain significant. Despite directed HP treatment, our patient demonstrated persistent malignacy and ultimately needed systemic chemotherapy.

Extranodal marginal zone b‐cell lymphoma of mucosa‐associated lymphoid tissue of the gallbladder

Mucosa‐associated lymphoid tissue (MALT) lymphoma of the gallbladder is rare with six cases reported in the English published reports. Most patients present with symptoms consistent with cholecystitis. We describe a case of extranodal marginal zone B‐cell lymphoma of MALT of the gallbladder in a 60‐year‐old woman who presented with abnormal liver function tests and subsequent finding of gallbladder thickening on ultrasonography. Cholecystectomy revealed a chronically inflamed gallbladder with multiple gallstones. Histology revealed abnormal sheets of small B lymphoid cells which were CD 20 positive, consistent with a diagnosis of MALT lymphoma. The pathogenesis of MALT lymphoma in the gallbladder remains controversial. As the gallbladder does not normally contain lymphocytes, persistent lymphoid proliferation due to chronic Gram‐negative infection may represent a critical step in the development and progression of MALT lymphoma. Cholecystectomy without adjuvant chemotherapy is the appropriate first line treatment if there is no other symptomatic disease.

The pathogenesis of MALT lymphomas: where do we stand?

Mucosa-associated lymphoid tissue (MALT) lymphoma is a heterogeneous form of a B-cell non-Hodgkin's lymphoma with extranodal location. The gastrointestinal tract is the most common site of disease, but involvement of multiple other organ systems has been documented. Four translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21) and t(3;14)(p13;q32), are specifically associated with MALT lymphoma. Remarkably, the genes targeted by at least three of these translocations are involved in one and the same pathway, leading to the activation of nuclear factor-kappaB (NF-kappaB). This review presents MALT lymphoma as a model of how sustained inflammation increases the risk of genotoxic insults and how these genetic events initiate oncogenesis.

Mucosa-Associated Lymphoid Tissue (MALT) Lymphoma

To review the pathogenesis of MALT lymphoma, and the associations with antigenic stimulation, presentation, and unique treatment. Research and review articles and textbooks. MALT lymphoma is a heterogeneous but unique pathologic form of extranodal B-cell non-Hodgkin's lymphoma. The gastrointestinal tract is the most common site of disease, but involvement of multiple other organ systems has been reported. In the case of gastric MALT lymphomas, H. pylori has been highly implicated as the stimulating agent. Treatment strategies for early disease involve eradication of H. pylori when it is involved and/or radiotherapy, which alone may result in cure of this lymphoma. Chemotherapy is used in more advanced or resistant disease. Nurses play a significant role in the education of patients about this unique malignancy and follow-up regarding compliance with therapy. Attention to social needs of the patients is critical.

Molecular pathogenesis of MALT lymphoma: two signaling pathways underlying the antiapoptotic effect of API2-MALT1 fusion protein

At least three recurrent chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), involving the API2-MALT1 fusion protein, BCL10 and MALT1, have been implicated in the pathogenesis of mucosa-associated lymphoid tissue (MALT) lymphoma. Several lines of evidence indicated that both BCL10 and MALT1 are required for nuclear factor kappa B (NF-kappaB) activation by antigen receptor stimulation in lymphocytes, and API2-MALT1 can bypass this BCL10/MALT1 signaling pathway. Nuclear factor kappa B activation may contribute to antiapoptotic effect through NF-kappaB-mediated upregulation of apoptotic inhibitor genes. We recently demonstrated that API2-MALT1 can induce transactivation of the API2 gene through NF-kappaB activation, thus highlighting a positive feedback-loop mechanism of self-activation by upregulating its own expression in t(11;18) MALT lymphomas. We also demonstrated that API2-MALT1 possesses an antiapoptotic effect, in part, through its direct interaction with apoptotic regulators. These findings therefore led us to hypothesize that the antiapoptotic effect by API2-MALT1 may be mediated by its interaction with apoptotic regulators, on the one hand, and by NF-kappaB-mediated upregulation of apoptotic inhibitor genes on the other. We also found that BCL10 and MALT1 are shuttling between nucleus and cytoplasm, and that MALT1 can regulate the subcellular location of BCL10.

MALT1 and BCL10 aberrations in MALT lymphomas and their effect on the expression of BCL10 in the tumour cells

Among the genetic abnormalities reported to occur in mucosa-associated lymphoid tissue (MALT) lymphomas, the three translocations t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) are of particular interest because they appear to be specific for, or at least closely related to this type of B-cell non-Hodgkin’s lymphoma. These translocations affect the MALT1 (18q21) and BCL10 (1p22) genes. We retrieved 77 consecutive biopsies of MALT lymphomas (documented with frozen material) over a 10-year period and investigated these cases for the presence of these three translocations with fluorescence in situ hybridisation, along with the immunohistochemical analysis of the intracellular localisation of the BCL10 protein. The above-listed translocations occurred mutually exclusive and were detected in 10, 1 and 3% of the cases, respectively (the latter incidence being much lower than in the previously reported studies by one single group). These genetic rearrangements corresponded well with the aberrant subcellular localisation of the BCL10 protein as found by immunohistochemistry: t(11;18)(q21;q21) and (1;14)(p22;q32) were marked by a, respectively, moderate to strong nuclear BCL10 staining pattern while t(14;18)(q32;q21)-positive MALT lymphomas were characterised by a perinuclear BCL10 staining pattern. This study further supports the close interaction between the MALT1 and BCL10 proteins in the pathogenesis of MALT lymphomas and may indicate that BCL10 immunohistochemistry is a simple technique to identify those MALT lymphoma cases with an underlying genetic aberration.

Anti-apoptotic action of API2-MALT1 fusion protein involved in t(11;18)(q21;q21) MALT lymphoma

At least three distinct chromosomal translocations, t(11;18)(q21;q21), t(1;14)(p22;q32) and t(14;18)(q32;q21) involving the API2 (also known as c-IAP2)-MALT1 fusion protein, BCL10, and MALT1, respectively, have been implicated in the molecular pathogenesis of mucosa associated lymphoid tissue (MALT) lymphoma. Our findings showed that several variants of the API2-MALT1 fusion protein can occur in patients with t(11;18)(q21;q21), and that API2-MALT1 can potently enfance activation of nuclear factor (NF)-kappaB signaling, which may be relevant to the pathogenesis of MALT lymphomas. We also found that MALT1 is rapidly degraded via the ubiquitin-proteasome pathway, as is the case with API2, but upon the synthesis of fusion, API2-MALT1 becomes stable against this pathway. This stability of API2-MALT1 may thus result in inappropriate nuclear factor (NF)-kappaB activation, thereby contributing to the pathogenesis of MALT lymphoma. Recent biochemical and genetic studies have clearly shown that BCL10 and MALT1 form a physical and functional complex and are both required for NF-kappaB activation by antigen receptor stimulation in T and B lymphocytes. It has also been shown that CARMA1, a newly discovered member of the membrane-associated guanylate kinase (MAGUK) families, is critical for antigen receptor-stimulated NF-kappaB activation. It can be assumed that API2-MALT1 can bypass this normal BCL10/MALT1 cellular signaling pathway linked to NF-kappaB activation, thereby inducing antigen receptor-independent proliferation of lymphocytes. Furthermore, BCL10/MALT1- and API2-MALT1-induced NF-kappaB activation may contribute to anti-apoptotic action probably through NF-kappaB-mediated upregulation of apoptotic inhibitor genes. We recently provided direct evidence that API2-MALT1 indeed exerts anti-apoptotic action, in part, through its direct interaction with apoptotic regulators including Smac. Taken together, these findings prompt us to hypothesize that the anti-apoptotic action of API2-MALT1 may be mediated partly by the direct interaction with apoptotic regulators as well as partly by upregulation of apoptotic inhibitor genes. Further studies can be expected to stimulate research into the development of therapeutic drugs that specifically inhibit the antigen receptor signaling-stimulated NF-kappaB activation pathway: such molecule targeting drugs should be useful for interfering with inappropriate proliferation of lymphocytes associated with inflammatory and neoplastic disorders.