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 t(11;14)(q13;q32) has been described in a spectrum of B-lymphoproliferative diseases and involves a putative oncogene, BCL1, which maps to chromosome band 11q13. Recent evidence indicates that this abnormality may delineate particular subtypes of lymphoma, such as intermediate lymphocytic and centrocytic lymphomas. Thus the possible significance of the t(11;14) within B-cell disorders should be reexamined in the light of a more objective approach to classifying these diseases by morphology, histology, and immunophenotype. We describe 16 patients with t(11;14)(q13;q32) from a series of 90 patients with chronic lymphoid disorders in whom clonal chromosome abnormalities were detected. All the cases were leukemic: prolymphocytic (B-PLL; 4/15 cases), chronic lymphocytic leukemia (CLL) with increase in prolymphocytes (2/9 cases), or non-Hodgkin lymphoma in leukemic phase, intermediate (3/4 cases), lymphoplasmacytic (2/2 cases), splenic lymphoma with villous lymphocytes (4/18 cases), and follicular (1 case). None of the CLL (25) or hairy cell leukemia cases (15) had t(11;14). Our findings showed that t(11;14) occurred in leukemias of mature B cells with lymphoplasmacytic features as judged by morphology and immunophenotype.
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PMID:Translocation t(11;14)(q13;q32) in chronic lymphoid disorders. 138 52

The chromosome 11q13 bcl-1 locus is rearranged in the majority of centrocytic lymphomas, a CD5-positive B-cell non-Hodgkins lymphoma, as a result of reciprocal translocation with the 14q32 immunoglobulin heavy chain genes. Although several 11q13 bcl-1 breakpoint sites have been characterized, a postulated bcl-1 oncogene was not identified. Recently, however, a gene encoding cyclin D1, designated PRAD1, was proposed as a candidate bcl-1 oncogene; accumulated evidence now indicates this gene is bcl-1. To further characterize 11q13 breakpoints in B-cell neoplasms, we analyzed 26 centrocytic lymphomas and 68 other B-cell cancers by Southern blot using a panel of breakpoint probes spanning 110 kilobases of the bcl-1 and PRAD1 loci. Nineteen centrocytic cases (73%) showed rearrangement, 15 at bcl-1 breakpoint sites and 5 at PRAD1 sites. One case was rearranged at both bcl-1 and PRAD1 loci. All but the latter case showed comigration of rearranged bcl-1 or PRAD1 bands and immunoglobulin heavy chain joining gene bands, consistent with the t(11;14). bcl-1 rearrangement was present in only one of 68 noncentrocytic B-cell neoplasms; none showed PRAD1 rearrangement. Thus, bcl-1 and PRAD1 rearrangement is strongly associated with centrocytic lymphoma, providing a useful molecular marker for classifying this subtype of lymphoma and suggesting an important role for PRAD1 cyclin D1 in the pathogenesis of this neoplasm.
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PMID:Characterization of chromosome 11 translocation breakpoints at the bcl-1 and PRAD1 loci in centrocytic lymphoma. 139 69

Indomethacin is a non-steroidal anti-inflammatory agent that inhibits prostaglandin synthesis. Administration of indomethacin, in doses which were non-toxic to normal BALB/c mice, to mice bearing the BCL1 leukemia resulted in increased mortality of these animals. This effect was only observed if the indomethacin was administered to animals with advanced disease (splenomegaly, hepatomegaly and leukemia). If indomethacin treatment was initiated prior to transplantation of the tumor or 2 weeks post-transplantation, and continued throughout the disease process, there was no effect on either the course of the disease or mortality. Injection of similar doses of indomethacin into mice bearing advanced B16 melanoma tumors did not result in increased mortality. Therefore, metabolic changes which occur in the leukemic animals may uniquely alter host sensitivity to this non-steroidal anti-inflammatory agent. The BCL1 leukemia may be a useful animal model to provide insights into the biochemical basis for the adverse reactions experienced by some Hodgkin's disease patients when they are treated with anti-inflammatory agents such as indomethacin.
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PMID:Increased sensitivity to indomethacin of mice bearing the BCL1-leukemia. 674 40

Immunohistochemical expression of PRAD1/cyclin D1 protein has been investigated in 106 tissue specimens of 104 cases of lymphoma, non-neoplastic lymphoid disorders and other hematologic malignancies by employing the monoclonal antibody 5D4 with formalin-fixed paraffin-embedded sections, using the microwave oven heating method. Positive neoplastic cells were found in 60 (74%) of 81 cases of non-Hodgkin's lymphoma. The positivity pattern was nuclear in 17 (85%) of 20 cases of mantle cell lymphoma in which cytoplasmic staining was also seen. This pattern of cyclin D1 positivity was in contrast to the negative staining of normal reactive mantle zones. In the other cases, positivity appeared to lie within the cell cytoplasm without nuclear staining, and most of the nodal follicular and diffuse B-cell lymphomas variously expressed PRAD1/cyclin D1. In contrast, the reaction was absent in a significant number of T-cell and extranodal B-cell lymphomas. Immunolocalization of PRAD1/cyclin D1 expression appears to be a useful diagnostic adjunct to discriminate mantle cell lymphoma from other non-Hodgkin's lymphomas.
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PMID:Immunohistochemical analysis of cyclin D1 protein in hematopoietic neoplasms with special reference to mantle cell lymphoma. 753 81

Mantle cell lymphoma (MCL) is a clinicopathologic entity that is difficult to diagnose on histopathologic criteria. Approximately 50% to 70% of MCL contain a t(11;14)(q13;q32) translocation involving the cyclin D1 gene. Irrespective of this rearrangement, almost all MCL show overexpression of the cyclin D1 gene at the mRNA level. Other B-cell non-Hodgkin's lymphomas (NHL) do not show this rearrangement or overexpression of cyclin D1. We developed an immunohistochemical assay to detect overexpression of the cyclin D1 protein on conventional formalin-fixed, paraffin-embedded biopsies using the well-defined monoclonal antibody DCS-6. Expression in tumor cells was compared with expression of cyclin D1 in endothelial cells and fibroblasts. An exclusively nuclear staining pattern was observed. Moreover, expression was directly compared with the expression observed by immunoblot analysis with the same antibody, as well as with mRNA expression and with the occurrence of genomic rearrangements within the BCL-1 locus. Of 13 MCL that were analyzed by immunohistochemistry and immunoblot, 12 showed overexpression with both techniques, whereas no overexpression was observed in 39 other NHL. Of 13 additional MCL studied either by immunohistochemistry or immunoblot, 11 also showed overexpression. Two lymphomas morphologically indistinguishable from MCL but with an aberrant immunophenotype (CD5 negative, CD10 positive) both lacked overexpression of cyclin D1. These results underscore the significance of overexpression of the cyclin D1 protein as a specific marker for MCL. Detection of cyclin D1 overexpression on formalin-fixed, paraffin-embedded tissues using the DCS-6 monoclonal antibody can be applied for routine diagnostic purposes.
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PMID:Cyclin D1 protein analysis in the diagnosis of mantle cell lymphoma. 767 Jan 10

In mantle cell lymphoma (MCL) a recurrent chromosomal rearrangement, t(11;14)(q13;q32), has been described. Most breakpoints have been detected within the 120 kb BCL-1 region, upstream of the cyclin D1 gene. To evaluate the association between BCL-1 rearrangement and expression of cyclin D1 in lymphoproliferative disorders, we analysed a series of 24 MCL, 56 other B-cell non-Hodgkin's lymphomas (NHL), 28 chronic B-cell leukemias, 18 hematopoietic cell lines and 10 normal lymphoid tissues at the RNA level. Hematopoietic cell lines with a known 11q13 translocation showed high expression of the 4.5 kb cyclin D1 transcript. Three B-cell lines without known 11q13 breakpoint showed low expression. We detected high expression in all (11/11) MCL with and in 11 out of 13 cases of MCL without detectable t(11;14) rearrangement. In three cases with a rearrangement at the 3' end of cyclin D1, two showed overexpression of the 1.5 kb transcript and one expression of an aberrant (3.0 kb) transcript. In other lymphoproliferative disorders, only 5/15 hairy cell leukemias, all without detectable t(11;14), and 5/8 B-cell leukemias suspected to be MCL in leukemic phase showed expression levels comparable to MCL, whereas no or only low expression were observed in 56 cases of other NHL, seven chronic B-cell leukemias and all (10/10) normal lymphoid tissues. Cell sorting experiments on fresh tonsils showed that this low expression was present in normal B-cells and not in T-cells. In contrast to other studies, our data indicate that cyclin D1 is expressed in many lymphoproliferative disorders and normal tissues, albeit at low levels. High levels of expression of cyclin D1 however is restricted to MCL and some hairy cell leukemias. We therefore propose that overexpression of cyclin D1 is a reliable marker for the classification of MCL.
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PMID:Cyclin D1 messenger RNA overexpression as a marker for mantle cell lymphoma. 775 58

Low-grade non-Hodgkin lymphomas (NHL) comprise a heterogeneous group of disorders both in terms of their cellular and histological composition as well as in terms of their clinical course. The most usually applied classification systems, the Working Formulation and the Kiel classification as well as the recently proposed Revised European American Lymphoma classification, discriminate between low-, intermediate- and high-grade subtypes. In general, low-grade NHL are characterized by a low to moderate proliferative activity and a long clinical course with median survival times ranging from approximately 3 years for centrocytic (CC) or mantle-cell lymphomas (MCL) to 5-8 years for centroblastic-centrocytic (CB-CC) or follicular lymphomas (FL). Recent cytogenetic and molecular biologic analyses indicate that these differences may result from distinct genetic abnormalities such as the translocation t(14;18), which is frequently observed in FL-NHL and is associated with a bcl-2 overexpression and inhibition of apoptosis, or the deregulation of PRAD1 in MCL-NHL induced by the translocation t(11;14). Therapy of low-grade lymphomas depends mainly on the extent of the disease. In the early stages I and II, at which approximately 15 to 20% of low-grade NHL are diagnosed, radiotherapy may be applied with curative intention. The treatment of patients with more advanced stages III and IV is controversial. The currently available information justifies a conservative approach of observing the natural course of the disease until therapeutic intervention is required due to the occurrence of B-symptoms, hematopoietic insufficiency or lymphoma progression.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Current status and future perspectives in the treatment of low-grade non-Hodgkin's lymphomas. 788 29

Histological subtyping of non-Hodgkin's lymphomas is of prognostic significance. Current classification systems subdivide them into low-, intermediate-, and high-grade malignancies. These subgroups are largely supported by clinical findings, but immunophenotyping and genotyping have shown that several of these histologically defined subcategories are heterogeneous. This is exemplified by the 'diffuse small cleaved-cell lymphoma' which comprises B-cell and T-cell lymphomas. Moreover, within the B-cell lymphomas, several entities have been included, which recapitulate the different compartments present in the reactive B follicle, e.g., the follicle centre, the mantle, and the marginal zone. Mantle-cell lymphomas have been identified in the United States as mantle-zone lymphomas and as intermediate differentiated lymphomas and in Europe as centrocytic lymphomas. Morphology, immunophenotyping, and cytogenetics of these three lymphomas support their similarity and underline their distinction from follicle centre-cell lymphomas as well as from small lymphocytic lymphomas. All three are composed of a mixture of small round and small cleaved cells, expressing several B-cell markers, surface immunoglobulins, and CD5, but lacking CD10 expression. They often carry the translocation t(11;14) with rearrangement of bcl-1/PRAD1 gene. The behaviour and responsiveness to therapy of mantle-cell lymphomas has not been fully documented yet. In order to obtain these data, precise subtyping of non-Hodgkin's lymphomas--not only based on morphology, but supported by immunophenotyping and cytogenetic analysis--is now mandatory.
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PMID:Mantle-cell lymphoma. 817 14

Centrocytic lymphoma (CC) and intermediately differentiated lymphocytic lymphoma (IDL) are B-cell non-Hodgkin's lymphomas composed of lymphocytes presumably derived from follicle mantle cells. In these lymphomas, a specific chromosomal translocation, t(11;14)(q13;q32), has been described. Previous studies suggested an association between t(11;14) chromosomal translocations and BCL-1 rearrangements. To evaluate the association between BCL-1 rearrangements and CC/IDL, Southern blot analysis was performed on a panel of 20 cases of CC/IDL, 22 cases of morphologically similar non-Hodgkin's lymphomas, 11 cases of chronic B-cell leukemias, and 2 cases of myelomas. We used various probes covering a considerable proportion of the 120-kilobase BCL-1 locus, and rearrangements in 50% of CC/IDL (10 of 20) were detected. In CC, all 4 breakpoints were located at the major translocation cluster (MTC). In contrast, in IDL, rearrangements were detected in 3 different cluster regions: 2 cases in the MTC, 2 cases with a breakpoint 24 kilobases outside the MTC, and 2 additional cases with breakpoints found 3 kilobases 5' of the first exon of the PRAD1/CCND1 gene, which is located 120 kilobases outside the MTC. In addition, one leukemia showed a breakpoint 63 kilobases outside the MTC. In all cases, there was comigration of the rearranged 11q13 fragment and the immunoglobulin heavy chain-joining gene complex, indicating a t(11;14)(q13;q32) chromosomal rearrangement. Our results show that Southern blot analysis is helpful to identify CC/IDL, but multiple breakpoints are present over a large region, and therefore, many probes are necessary to cover all breakpoints.
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PMID:Multiple breakpoints within the BCL-1 locus in B-cell lymphoma: rearrangements of the cyclin D1 gene. 836 7

BCL1/PRAD1 gene rearrangements involving the cyclin D1 gene are a feature of about 70% of centrocytic/mantle-cell lymphomas (CC/MCL) but are identified in only a small proportion of other B-cell non-Hodgkin's lymphomas. Of 37 lymphomas found to have BCL1/cyclin D1 (PRAD1, CCND1) gene rearrangements, 30 fit the morphologic and immunophenotypic criteria for typical CC/MCL. Seven cases with morphologic features atypical for CC/MCL were identified. CD5+ monoclonal B cells were documented in all these cases. Six cases were subsequently stained for cyclin D1 protein, and all showed nuclear positivity. Five cases had variably sized foci of cells with moderately abundant pale cytoplasm resembling parafollicular/monocytoid B cells, marginal zone cells, hairy cells, or even proliferation centers. Transformed-appearing cells were also present in some lymphomas. In one case, striking follicular colonization created a markedly nodular growth pattern mimicking a follicular lymphoma. A sixth case had a marked predominance of small, round lymphocytes at some sites, mimicking a small lymphocytic lymphoma. Five of these six cases also had areas more typical of CC/MCL. The seventh case was a CD5-positive splenic marginal zone-like lymphoma (SMZL) with plasmacytic differentiation and circulating villous lymphocytes consistent with a splenic lymphoma with villous lymphocytes (SLVL). These cases illustrate the morphologic spectrum of small B-cell lymphoid neoplasms that have BCL1/cyclin D1 gene rearrangements and overexpression of cyclin D1. Despite the BCL1 translocation and cyclin D1 overexpression, the splenic lymphoma with plasmacytic differentiation was definitely not a CC/MCL and fit the clinicopathologic entity of SMZL/SLVL. The other six cases are best considered CC/MCL variants based on a combined morphologic, immunophenotypic, and genotypic evaluation. Genotypic or immunophenotypic studies to identify cyclin D1 rearrangements and overexpression, although not pathognomonic, are useful in recognizing these variant CC/MCL cases, which can mimic almost any of the other well-described but more indolent low-grade B-cell lymphomas and leukemias. Some of the variant CC/MCL cases had features in common with the CD5+ cyclin D1+ SMZL/SLVL, suggesting a possible relationship between these two otherwise distinct entities.
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PMID:The morphologic spectrum of non-Hodgkin's lymphomas with BCL1/cyclin D1 gene rearrangements. 861 27


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