Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The translocation of chromosome 11, long arm, region 2, band 1, to chromosome 18, long arm, region 2, band 1 (t(11;18)(q21;q21)) represents a recurrent chromosomal abnormality in extranodal marginal zone B-cell lymphoma (MZBCL) of mucosa-associated lymphoid tissue (MALT) type and leads to a fusion of the apoptosis inhibitor-2 (API2) gene on chromosome 11 and the MALT lymphoma-associated translocation (MLT) gene on chromosome 18. A 2-color fluorescence in situ hybridization (FISH) assay, which can be used for the detection of t(11;18) in interphase nuclei and metaphase chromosomes on fresh and archival tumor tissue, was developed. The P1 artificial chromosome (PAC) clone located immediately telomeric to the MLT gene and the PAC clone spanning the API2 gene were differentially labeled and used to visualize the derivative chromosome 11 resulting from t(11;18), as evident by the overlapping or juxtaposed red and green fluorescent signals. The assay was applied to interphase nuclei of 20 cases with nonmalignant conditions and 122 B-cell non-Hodgkin's lymphomas (NHLs). The latter group comprised 20 cases of nodal follicle center cell lymphoma and diffuse large B-cell NHL, 10 cases of gastric diffuse large B-cell lymphoma, 10 cases of hairy cell leukemia, and 82 cases of MZBCL (41 extranodal from various locations, 19 nodal, and 22 splenic MZBCL) including 35 cases with an abnormal karyotype, 2 of which revealed t(11;18). By interphase FISH, t(11;18) was detected in 8 gastrointestinal low-grade MALT-type lymphomas including the 2 cytogenetically t(11;18)(+) cases. In the 8 t(11;18)(+) cases, the FISH results were confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) using API2 and MLT specific primers. Our results indicate that t(11;18)(q21;q21) specifically characterizes a subgroup of low-grade MZBCL of the MALT-type and that the FISH assay described here is a highly specific and rapid test for the detection of this translocation.
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PMID:Detection of t(11;18)(q21;q21) by interphase fluorescence in situ hybridization using API2 and MLT specific probes. 1097 68

The translocation t(11;18)(q21;q21), which is the most frequent chromosomal aberration in extranodal marginal zone B cell lymphomas of MALT-type, was characterised in a series of 34 biopsies, including 18 gastric non-Hodgkin's lymphomas (NHL) of MALT-type, six MALT-type NHL of extragastral origin and 10 extranodal large B cell lymphomas (LBL). Based on fluorescence in situ hybridisation, STS-PCR analysis and screening of genomic PAC libraries, a physical map of contiguous DNA probes on chromosome 11 was constructed containing the anti-apoptotic genes API2 and API1 adjacent to the translocation breakpoint. RACE-PCR experiments revealed MALT1 the chromosome 18-derived fusion partner of API2, which has also been reported recently by other groups. RT-PCR analysis and DNA sequencing demonstrated the expression of an API2-MALT1 fusion transcript in 18/24 gastral and extragastral MALT-type lymphomas. In none of 10 LBLs was a translocation specific RT-PCR product detected. Five variants of the fusion transcript were identified and in all instances the open reading frame of the fused portion of the MALT1 gene was maintained. The molecular analysis of these variants allowed the design of optimised assays for the diagnosis of the API2-MALT1 gene rearrangement.
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PMID:Heterogeneity of the API2-MALT1 gene rearrangement in MALT-type lymphoma. 1106 33

The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL. In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly. In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues. In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel "proto-oncogenes" involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcgammaRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.
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PMID:Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma. 1170 42

The MALT1 gene was identified through its involvement in t(11;18)(q21;q21), seen in 30% of cases of mucosa-associated lymphoid tissue (MALT) lymphoma. Here, we show that deregulated MALT1 expression may occur in B-cell non-Hodgkin lymphoma (B-NHL) of various histologic subtypes either through translocation to the immunoglobulin heavy chain (IGH) locus or by genomic amplification. First, 2 cases, one case of MALT lymphoma and another of aggressive marginal zone lymphoma (MZL) with t(14;18)(q32;q21), cytogenetically identical to the translocation involving BCL2, were shown by fluorescence in situ hybridization (FISH) to involve MALT1, which lies about 5 Mb centromeric of BCL2. Molecular cloning of both by long-distance inverse polymerase chain reaction showed breakpoints lying 1 to 2 kilobase (kb) centromeric of the first 5' MALT1 exon; both cases showed MALT1 overexpression at either RNA or protein levels. Second, we examined the structure and gene expression profile of genomic amplifications involving 18q21 in a panel of 40 B-NHL cell lines using comparative genomic hybridization to microarrays (array CGH) and gene expression profiling techniques. Using array CGH, 2 peaks of genomic amplification were observed, one centered around BCL2 and the other around MALT1. Ofthe 3 cell lines with MALT1 amplification, 2 showed MALT1 overexpression as assessed by gene profiling, quantitative reverse transcription-polymerase chain reaction (QRT-PCR), and Western blotting. To determine if comparable events occurred in primary MALT and splenic MZL tumors, 40 cases were analyzed by FISH or QRT-PCR; genomic amplification and MALT1 overexpression were seen in 2 cases. Together, these data implicate MALT1 as a dominant oncogene that may play a role in the pathogenesis of B-NHL.
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PMID:MALT1 is deregulated by both chromosomal translocation and amplification in B-cell non-Hodgkin lymphoma. 1256 Feb 19

The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor kappaB (NF-kappa B) signaling, but this has not been shown experimentally in human B cells. Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-kappa B signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-kappa B activity and enhanced I kappa B kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-kappa B cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative I kappa B alpha mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-kappa B activity. Our findings support a model in which NF-kappa B signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.
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PMID:MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. 1559 10

Gain of chromosome 18q and translocation t(14;18) are] frequently found in B-cell non-Hodgkin's lymphomas (B-NHL). Increased BCL2 transcription and BCL2 protein expression have been suggested to be the result of the gain. We utilized FISH, PCR and array CGH to study BCL2 and chromosome 18 copy number changes and rearrangements in 93 cases of B-NHL. BCL2 protein was expressed in >75% of the tumor cells in 92% of the cases by immunohistochemistry. Gain of BCL2 was associated with a 25% increase in BCL2 expression levels (immunoblotting), whereas t(14;18) resulted in a 55% increase in BCL2 levels compared to cases without BCL2 alterations. The tumor cell (spontaneous) apoptotic fractions were similar for the cases with different BCL2 genotypes. However, the normal cell apoptotic fractions were higher for the tumors with t(14;18) compared to the tumors without BCL2 alterations, while the tumors with gain of BCL2 only showed intermediate levels. Low-level gains of parts of chromosome 18 were found in 14 of the 38 B-NHL cases with t(14;18), with a consensus region 18pter-q21.33 that did not include the BCL2 gene. The 11 cases with 18q gain only showed a consensus region encompassing 18q21.2-18q21.32 and 18q21.33, which contain PMAIP1/MALT1 and BCL2, respectively.
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PMID:Translocation t(14;18) and gain of chromosome 18/BCL2: effects on BCL2 expression and apoptosis in B-cell non-Hodgkin's lymphomas. 1619 90

Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphomas are a well-described type of low-grade B-cell non-Hodgkin lymphoma. They typically arise adjacent to mucosal surfaces in the gastrointestinal tract, lung and conjunctiva, and, less frequently, in the skin, salivary gland and thyroid gland. Unusual locations, such as the genitourinary tract, thymus and meninges, have also been reported. We recently encountered a case of an intracranial MALT lymphoma in a 53-year-old man who presented with persistent headaches and a seizure. The lesion developed as a mass within the lateral ventricle, appeared to be arising from the choroid plexus, and was not associated with meninges. Histologically, there was a vaguely nodular, dense lymphoid infiltrate with occasional benign follicles colonized by marginal zone lymphoma, suggesting derivation from a focus of prior inflammation. Translocations involving the MALT1 gene were not identified but karyotypic evaluation highlighted a complex cytogenetic profile with many chromosomal abnormalities. This rare case provides insight into the pathophysiology of MALT lymphomas.
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PMID:Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue arising in the lateral ventricle. 1619 87

Marginal zone mucosa-associated lymphoid tissue (MALT) B-cell lymphoma is the most common extranodal non-Hodgkin lymphoma. The t(11;18)(q21;q21) translocation occurs frequently in MALT lymphomas and creates a chimeric NF-kappaB-activating protein containing the baculoviral IAP repeat (BIR) domains of c-IAP2 (inhibitor of apoptosis protein 2) fused with portions of the MALT1 protein. The BIR1 domain of c-IAP2 interacts directly with TRAF2 (TNFalpha-receptor-associated factor-2), but its role in NF-kappaB activation is still unclear. Here, we investigated the role of TRAF2 in c-IAP2/MALT1-induced NF-kappaB activation. We show the BIR1 domain of c-IAP2 is essential for NF-kappaB activation, whereas BIR2 and BIR3 domains are not. Studies of c-IAP2/MALT1 BIR1 mutant (E47A/R48A) that fails to activate NF-kappaB showed loss of TRAF2 binding, but retention of TRAF6 binding, suggesting that interaction of c-IAP2/MALT1 with TRAF6 is insufficient for NF-kappaB induction. In addition, a dominant-negative TRAF2 mutant or downregulation of TRAF2 achieved by small interfering RNA inhibited NF-kappaB activation by c-IAP2/MALT1 showing that TRAF2 is indispensable. Comparisons of the bioactivity of intact c-IAP2/MALT1 oncoprotein and BIR1 E47A/R48A c-IAP2/MALT1 mutant that cannot bind TRAF2 in a lymphoid cell line provided evidence that TRAF2 interaction is critical for c-IAP2/MALT1-mediated increases in the NF-kappaB activity, increased expression of endogenous NF-kappaB target genes (c-FLIP, TRAF1), and resistance to apoptosis.
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PMID:TRAF2-binding BIR1 domain of c-IAP2/MALT1 fusion protein is essential for activation of NF-kappaB. 1923 89

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma involving brain, intraocular structures and spinal cord, without evidence of systemic disease. The majority of PCNSLs are diffuse large B-cell type. We encountered a rare case of primary dural marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) with extension into the brain in a 59-year-old man. A magnetic resonance imaging scan showed a 22-mm tumor located in the left posterior temporal lobe extending from the dura. Histopathology revealed a lymphoplasmacytic infiltration of the dura and the brain parenchyma in a perivascular pattern. Immunohistochemical and in situ hybridization studies showed a B-cell phenotype with kappa light chain restriction. Fluorescent in situ hybridization study showed a t(14;18)(q32;q21) with immunoglobulin heavy-chain/MALT1 fusion. The molecular study for immunoglobulin heavy-chain gene rearrangement by polymerase chain reaction showed a clonal gene rearrangement.
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PMID:Extranodal marginal zone lymphoma of the dura mater with IgH/MALT1 translocation and review of literature. 1966 12

Mucosa-associated lymphoid tissue (MALT) lymphoma is a type of B-cell non-Hodgkin lymphoma that can originate in the gastrointestinal (GI) tract, thyroid, breasts, lungs, and skin. The most common genetic abnormality occurring in MALT lymphomas involves t(11;18)(q21;q21) in the gene MALT1. This translocation results in a chimeric fusion product between the genes ATI2 and MALT1, which generates a survival advantage in the lymphoma cells. The MALT1 disruption is more common in some MALT lymphomas, distinguished by site, than others. If identified, this variation in frequency could affect treatment courses and outcomes for each type of MALT lymphoma. The study included 109 MALT lymphoma sample specimens. The sample paraffin-embedded slides were pretreated, hybridized for FISH using a MALT1 break-apart probe, post-washed, and viewed using a fluorescent microscope. On each slide, 100 individual cells were counted by two independent readers, totaling 200 cells per case, and the percentage of cells containing a translocation within each sample was recorded. A conservative threshold of 8% was used to make a positive call. There were a total of 18 positive results in the 109 samples tested. The tissue specimens tested that yielded positive results include the colon (62.5%), lung (57.14%), skin (25%), eyelid/lacrimal gland (16.67%), stomach (6.45%), kidney (50%), and thyroid (100%). The sites that yielded only negative results (0%) include the breast, salivary gland, salivary gland/parotid, soft tissue/skin, conjunctiva/orbital, small intestine, nasal, and epidural mass. As hypothesized, a variation in the MALT1 disruption was found. This is the first study to examine MALT1 disruption in the soft tissue, nasal, and epidural mass. The positive results of this study, specifically the results for the colon and lung, and the negative breast and salivary gland results are consistent with previous studies examining the genetic aberrations in MALT lymphomas. These results indicate that MALT lymphoma at different locations differentially display MALT1 disruption, and these disruptions may be responsible for the variance in patient response to therapy. Surgery, radiation therapy, and/or administration of cladribine (2CdA) result in the best outcomes in treating MALT lymphomas with MALT1 disruption.
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PMID:Variations in MALT1 Gene Disruptions Detected by FISH in 109 MALT Lymphomas Occurring in Different Primary Sites. 2165 70


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