Bcl10 and MALT1, Independent Targets of Chromosomal Translocation in MALT Lymphoma, Cooperate in a Novel NF-κB Signaling Pathway

Lucas, Peter C.; Yonezumi, Masakatsu; Inohara, Naohiro; McAllister-Lucas, Linda M.; Abazeed, Mohamed E.; Chen, Felicia F.; Shoji, Yasuhiro; Seto, Masao; Núñez, Gabriel

doi:10.1074/jbc.m009984200

Cited by 394 publications

(420 citation statements)

References 37 publications

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“…The API2 moiety of API2-MALT1 mediates oligomerization via a non-homotypic interaction In the absence of Bcl10, wild-type MALT1 does not activate NF-kB (Uren et al, 2000;Lucas et al, 2001). It is thought that upon antigenic stimulation, Bcl10 binds Multiple roles for the API2 moiety of API2-MALT1 PC Lucas et al to MALT1 and induces its oligomerization and that enforced oligomerization of the MALT1 C-terminus triggers NF-kB activation Sun et al, 2004).…”

Section: Resultsmentioning

confidence: 99%

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A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment

Lucas

Kuffa

et al. 2007

Oncogene

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Mucosa-associated lymphoid tissue (MALT) lymphoma is the most common extranodal lymphoid neoplasm. Chromosomal translocation t(11;18)(q21,q21) is found in 30% of gastric MALT lymphomas and is associated with a failure to respond to standard treatment and a tendency to disseminate. This translocation generates a chimeric protein composed of N-terminal sequences of Inhibitor of Apoptosis 2 (API2, also known as BIRC3 and cIAP2) fused to C-terminal sequences of MALT1. API2-MALT1 promotes cell survival and proliferation via activation of nuclear factor-jB (NF-jB). Here, we investigate the mechanism by which the API2 moiety contributes to NF-jB stimulation. We find that the API2 moiety mediates oligomerization of API2-MALT1 as well as interaction with tumor necrosis factor receptor-associated factor 2 (TRAF2). Surprisingly, oligomerization does not occur via homotypic interaction; rather, the API2 moiety of one monomer interacts with the MALT1 moiety of another monomer. Further, the specific region of the API2 moiety responsible for mediating oligomerization is distinct from that mediating TRAF2 binding. Although deletion or mutation of the TRAF2 binding site does not inhibit oligomerization, it does lead to dramatically decreased NF-jB activation. Deletion of both TRAF2 binding and oligomerization regions results in nearcomplete loss of NF-jB activation. Thus, API2 moietymediated heterotypic oligomerization and TRAF2 binding both contribute to maximal API2-MALT1-dependent NF-jB stimulation.

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Section: Resultsmentioning

confidence: 99%

“…Unlike wild-type MALT1, which must interact with Bcl10 to activate NF-kB, API2-MALT1 potently stimulates NF-kB in the absence of Bcl10 (Uren et al, 2000;Lucas et al, 2001;Ruland et al, 2003). This suggests that API2-MALT1 may represent a gain-offunction mutant that promotes lymphomagenesis through inappropriate NF-kB activation.…”

Section: Introductionmentioning

confidence: 99%

A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment

Lucas

Kuffa

et al. 2007

Oncogene

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“…3,4 API2 is a member of the IAP (inhibitor of apoptosis) gene family, and is essential for the suppression of apoptosis. 5 MALT1, a novel gene, may be involved in NF kappa B activation, 6 however, its biological function is not fully elucidated. Recent data have shown that API2-MALT1 fusion leads to an increased inhibition of apoptosis, which thereby helps MALT lymphomas to survive.…”

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confidence: 99%

Immunoglobulin VH gene analysis in gastric MALT lymphomas

et al. 2007

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The majority of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are successfully treated with Helicobacter pylori eradication alone. However, certain subsets of these tumors are resistant to the eradication treatment. As API2-MALT1 fusion is a feature of one of these subsets, we divided gastric MALT lymphomas into three groups: eradication-responsive and API2-MALT1 fusion-negative (Group A), eradication-resistant and fusion-negative (Group B), and eradication-resistant and fusion-positive (Group C). To characterize further gastric MALT lymphomas, we analyzed VH genes, which do not change in the course of tumor progression, by extensive subcloning of the monoclonal PCR products of 45 cases. VH3-23 and VH3-30 were preferentially used in Group A tumors (14/23 cases, 61%) as compared with Group B (1/10 cases, 10%, P ¼ 0.0094) and Group C (2/ 12 cases, 17%, P ¼ 0.017). Tumors of Groups B and C used variegated VH fragments, and no dominant VH fragments were noted. Somatic mutation was detected in most of the cases. Ongoing mutation was detected in 3/45 cases (7%), when assessed according to strict criteria for a confirmed mutation. These findings suggest that inflammation-dependent tumors (Group A) may be derived from a highly restricted, probably H. pyloriassociated, B cell subset and may not often progress to those that are inflammation-independent (Groups B and C). Although considered to be common in this tumor, ongoing mutation may be infrequent when assessed by strict criteria. Keywords: gastric MALT lymphoma; helicobacter pylori; eradication; immunoglobulin heavy chain variable genes; API2-MALT1 fusion gene Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a distinct low-grade lymphoma, which is typically localized long term at the site of origin. 1 A preexisting chronic inflammation, such as Helicobacter pylori gastritis, Hashimoto's thyroiditis, or Sjogren's syndrome is considered to influence significantly its development. 1 The etiological link between gastric MALT lymphoma and H. pylori gastritis has arisen from the fact that the majority of gastric MALT lymphomas (approximately 70% of cases) show complete regression on eradication of H. pylori alone. 2 API2-MALT1 fusion, cloned from t(11;18)(q21;q21), is a gene alteration specific to MALT lymphomas. 3,4 API2 is a member of the IAP (inhibitor of apoptosis) gene family, and is essential for the suppression of apoptosis. 5 MALT1, a novel

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“…Conversely, the fusion products containing the Ig-like MALT1 domains are more potent activators of NF-kB than those without. 15,31 Moreover, tumors bearing the fusion product with one or two intact Ig-like domains have more advanced stage than those without. 32 Therefore, the two gastric MALT lymphomas with MALT1 break point in intron 7 that belongs to group A might have acquired additional yet unidentified genetic changes which may cause expression profiles comparable to the four gastric MALT lymphoma cases with MALT1 break point in intron 4.…”

Section: Discussionmentioning

confidence: 99%

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

et al. 2010

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Among the genetic abnormalities reported to occur in MALT lymphomas, the translocation t(11;18)(q21;q21) is of particular interest because it is exclusively documented in MALT lymphomas, mainly with gastrointestinal location. It results in the creation of a fusion protein API2-MALT1 that activates the transcription factor NF-jB through enhanced IKKc polyubiquitination. Here, we apply the recently developed molecular technique termed comparative expressed sequence hybridization to identify differentially expressed chromosomal regions related to the pathogenesis of gastric MALT lymphomas. By comparing t(11;18)(q21;q21)-positive gastric MALT lymphomas to their t(11;18)(q21;q21)-negative counterparts, we found that the location of the MALT1 break point determines a difference in expression pattern within the t(11;18)(q21;q21)-positive group. Moreover, we could define a gastric MALT lymphoma signature, which most likely comprises the regions and genes with significance in the development of MALT lymphomas, by comparing both t(11;18)(q21;q21)-positive and -negative MALT lymphomas to normal lymphoid tissue. Finally, a significant imprint of the marginal zone signature, established by comparing microdissected, splenic B follicles with and without marginal zone, was evident in the expression profile of MALT lymphoma, further supporting a marginal zone origin for this type of B-cell non-Hodgkin's lymphoma.

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Bcl10 and MALT1, Independent Targets of Chromosomal Translocation in MALT Lymphoma, Cooperate in a Novel NF-κB Signaling Pathway

Cited by 394 publications

References 37 publications

A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment

A dual role for the API2 moiety in API2-MALT1-dependent NF-κB activation: heterotypic oligomerization and TRAF2 recruitment

Immunoglobulin VH gene analysis in gastric MALT lymphomas

Comparative expressed sequence hybridization studies of t(11;18)(q21;q21)-positive and -negative gastric MALT lymphomas reveal both unique and overlapping gene programs

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