Angioimmunoblastic T-cell lymphoma (AITL) is a systemic disease involving lymph nodes, spleen, and bone marrow. Although the histologic features have been well described, the diagnosis is often challenging, as there are no specific phenotypic or molecular markers available. This study shows that the neoplas-

In a previous study, it was shown that the Kaposi sarcoma-associated herpesvirus (KSHV) was specifically associated with monotypic (IgM) plasmablasts in multicentric Castleman disease (

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t(11;18)(q21;q21) is a specific chromosomal translocation associated with mucosa-associated lymphoid tissue (MALT) lymphoma. It fuses the amino terminal of the API2 gene to the carboxyl terminal of the MALT1 gene and generates a chimeric fusion product. Although the translocation is frequently detected in gastric and pulmonary MALT lymphoma, its incidence in MALT lymphomas from other sites is largely unknown. It also remains unknown whether the occurrence of the translocation is influenced by the nature of preceding diseases associated with MALT lymphomas. We screened for t(11; 18)(q21;q21) in 417 cases of MALT lymphoma from 8 major sites by reverse transcription-polymerase chain reaction. t(11;18)(q21;q21) was found at highest frequencies in MALT lymphomas from the lung (38%) and stomach (24%), and at moderate frequencies in those from the conjunctiva (19%) and orbit (14%). However, the translocation was found only rarely in MALT lymphomas from the salivary gland (1%) and was absent in those from the thyroid, skin, liver, and other rare sites, and in immunoproliferative small intestinal disease (IPSID). In gastric MALT lymphoma, t(11;18)(q21;q21) was significantly associated with infection by CagA-positive strains of Helicobacter pylori. As CagA-positive strains of H pylori are much more potent in induction of host inflammatory responses, including activation of neutrophils, which release highly genotoxic oxygen reactive species, we therefore examined neutrophil infiltration in recognized precursors of MALT lymphoma including H pylori-associated gastritis, lymphoepithelial sialadenitis, and Hashimoto thyroiditis. Neutrophil infiltration was prominent in H pylori-associated gastritis but not in lymphoepithelial sialadenitis and Hashimoto thyroiditis. Our results demonstrate that t(11;18)(q21; q21) occurs at markedly variable frequencies in MALT lymphoma of different sites and suggest that the occurrence of the translocation is influenced by the nature of premalignant diseases associated with MALT lymphoma. Oxidative damage might play a role in development of t(11;18)(q21; q21).

The development of gastric mucosaassociated lymphoid tissue (MALT) lymphoma is a multistep process and can be clinico-pathologically divided into Helicobacter pylori-associated gastritis, lowgrade tumors, and high-grade tumors. The molecular events underlying this progression are largely unknown. However, identification of the genes involved in MALT lymphoma-specific t(11;18)(q21; q21) and t(1;14)(p22;q32) has provided fresh insights into the pathogenesis of this disease. T(11;18)(q21;q21) results in a chimeric transcript between the API2 and the MALT1 genes, whereas t(1;14) (p22;q32) causes aberrant nuclear BCL10 expression. Significantly, nuclear BCL10 expression also occurs frequently in MALT lymphomas without t(1;14)(p22; q32), suggesting an important role for BCL10 in lymphoma development. Thirtythree cases of H pylori gastritis, 72 MALT lymphomas, and 11 mucosal diffuse large B-cell lymphomas (DLBCL) were screened for t(11;18)(q21;q21) by reverse transcription-polymerase chain reaction followed by sequencing. BCL10 expression in lymphoma cases was examined by immunohistochemistry. The API2-MALT1 fusion transcript was not detected in H pylori gastritis and mucosal DLBCL but was found in 25 of 72 (35%) MALT lymphomas of various sites. Nuclear BCL10 expression was seen in 28 of 53 (53%) of MALT lymphomas. Of the gastric cases, the largest group studied, the frequency of both t(11;18)(q21;q21) and nuclear BCL10 expression was significantly higher in tumors that showed dissemination to local lymph nodes or distal sites (14 of 18 ‫؍‬ 78% and 14 of 15 ‫؍‬ 93%, respectively) than those confined to the stomach (3 of 29 ‫؍‬ 10% and 10 of 26 ‫؍‬ 38%). Furthermore, t(11;18)(q21;q21) closely correlated with BCL10 nuclear expression. These results indicate that both t(11;18)(q21;q21) and BCL10 nuclear expression are associated with advanced MALT lymphoma and that their oncogenic activities may be related to each other. IntroductionThe development of mucosa-associated lymphoid tissue (MALT) lymphoma is a multistage process. 1 This is best understood in gastric MALT lymphoma, the most common form. Typically, low-grade gastric MALT lymphoma arises from mucosal lymphoid tissue that is acquired usually as a reaction to Helicobacter pylori infection. 2,3 Low-grade MALT lymphoma is initially confined to the gastric mucosa, and its growth depends critically on the contact help of H pylori-specific intratumoral T cells; therefore, it responds favorably to H pylori eradication therapy. [4][5][6] However, when the lymphoma invades the deep layers of the gastric wall and disseminates to local lymph nodes and distal sites, the tumor loses its dependence on H pylori-specific T cells and is no longer sensitive to H pylori eradication therapy. 7-9 Finally, low-grade gastric MALT lymphoma may transform into a more aggressive diffuse large B-cell lymphoma (DLBCL). 10,11 Direct 12-14 and indirect antigen stimulation 4,5 and several genetic factors, including genetic instability, 15 trisomy 3, 16 p53 mutation/LOH, 17 p16 deletion, 18 t(1;...

␤-catenin ͉ Lef1 ͉ Wnt10b ͉ fungiform papilla

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Exonic splicing enhancers (ESEs) are important cis elements required for exon inclusion. Using an in vitro functional selection and amplification procedure, we have identified a novel ESE motif recognized by the human SR protein SC35 under splicing conditions. The selected sequences are functional and specific: they promote splicing in nuclear extract or in S100 extract complemented by SC35 but not by SF2/ASF. They can also function in a different exonic context from the one used for the selection procedure. The selected sequences share one or two close matches to a short and highly degenerate octamer consensus, GRYYcSYR. A score matrix was generated from the selected sequences according to the nucleotide frequency at each position of their best match to the consensus motif. The SC35 score matrix, along with our previously reported SF2/ASF score matrix, was used to search the sequences of two well-characterized splicing substrates derived from the mouse immunoglobulin M (IgM) and human immunodeficiency virus tat genes. Multiple SC35 high-score motifs, but only two widely separated SF2/ASF motifs, were found in the IgM C4 exon, which can be spliced in S100 extract complemented by SC35. In contrast, multiple high-score motifs for both SF2/ASF and SC35 were found in a variant of the Tat T3 exon (lacking an SC35-specific silencer) whose splicing can be complemented by either SF2/ASF or SC35. The motif score matrix can help locate SC35-specific enhancers in natural exon sequences.Accurate removal of introns from pre-mRNA requires multiple cis elements, including the splice sites, polypyrimidine tract, branch site, and other intronic and exonic sequences that have positive or negative effects on splicing (10, 31, 44; reviewed in references 1 and 2). Positive-acting sequences, termed exonic splicing enhancers (ESEs) (37,39,42), have been identified primarily in exons associated with regulated splicing. These exons are typically adjacent to introns with weak intronic splicing signals and require ESEs for their inclusion. Deletion of an ESE often causes exon skipping or, in the case of terminal exons, suppresses removal of the last intron. One of the first characterized ESEs is located in the M2 3Ј-terminal exon of the mouse immunoglobulin M (IgM) gene (39). This 73-nucleotide (nt) ESE, which is highly purine rich, is required for inclusion of the alternatively spliced M2 exon. However, deletion of just the purine-rich sequences within this ESE does not abolish splicing completely. The M2 ESE also functions in a heterologous context to enhance splicing of a Drosophila melanogaster doublesex intron (39).A SELEX procedure has been used to identify sequences that can function as ESEs (36). A 20-nt sequence of the internal duplicated exon of a model pre-mRNA was replaced by 20 nt of random sequence. The randomized pre-mRNAs were incubated under splicing conditions in nuclear extract, and functional enhancer elements that promoted splicing were selected. A large number of sequences, both purine rich and non-purine rich were o...