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

The fusion gene NPM-ALK occurs in a subset of anaplastic large cell lymphomas (ALCLs), as a result of a chromosomal translocation, t(2;5) (p23;q35). It has been suggested that Hodgkin's disease (HD) and ALCL share a common histogenesis because of pathological and phenotypical similarities. In order to check this hypothesis, reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to detect the hybrid NPM-ALK gene in 30 tumour samples, including 22 lymph node biopsies from HD and eight ALCL specimens. The threshold level of sensitivity was shown to reach at least 1/10(4) by dilution experiments using cell lines as positive and negative controls. The expected 177 bp product indicative of the NPM-ALK rearrangement was identified in Karpas 299 and SUDHL-1 cell lines and in two out of eight ALCLs. The 22 HD cases were negative, even after two successive tests. Thus, since the ALCL-specific genetic alteration was absent in our series of HD cases, the present study does not support the hypothesis that HD and ALCL are histogenetically related entities.
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PMID:Molecular analysis of the NPM-ALK rearrangement in Hodgkin's disease. 868 74

The t(2;5) (p23;q35) chromosomal translocation has been found in a high proportion of lymph node-based CD30+ large cell lymphomas of T-cell lineage. This translocation is believed to result in the expression of a fusion protein containing the catalytic domain of anaplastic lymphoma kinase (ALK) under the control of the promoter for nucleophosmin, a nucleolar phosphoprotein. Expression of ALK activity, which does not normally occur in lymphocytes, is postulated to be involved in the pathogenesis of lymphomas bearing the t(2;5) translocation. Several primary cutaneous lymphoproliferative disorders and Hodgkin's disease are also known to contain CD30+ large lymphoid cells. To determine the role of the t(2;5) translocation in these diseases, we developed a DNA-based polymerase chain reaction (PCR)/Southern blot assay to detect this translocation at the genomic level in lymphomatoid papulosis (14 cases), primary cutaneous CD30+ large cell lymphoma of T-lineage (10 cases) and Hodgkin's disease (13 cases). Two cases of pityriasis lichenoides were also studied. The t(2;5) translocation was not present in any of these specimens. To determine if some other somatic mutation might have resulted in inappropriate expression of ALK catalytic domain, we devised an RNA-based reverse transcriptase-PCR assay to detect transcripts encoded by this ALK region. None were found in the six additional cases of lymphomatoid papulosis that were studied. In aggregate, these results strongly suggest that inappropriate expression of ALK is not involved in the pathogenesis of these CD30+ lymphoproliferative disorders, and that lymph node-based CD30+ large cell lymphoma is a disease that is biologically distinct from skin-based CD30+ lymphoproliferative disorders and Hodgkin's disease. Using methods developed for this report, we also cloned and sequenced the t(2;5) genomic junctional sequences present in the SUP-M2 and SU-DHL-1 cell lines. These intron sequences will be useful for mapping t(2;5) breakpoint clusters.
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PMID:Lack of the t(2;5) or other mutations resulting in expression of anaplastic lymphoma kinase catalytic domain in CD30+ primary cutaneous lymphoproliferative disorders and Hodgkin's disease. 878 33

Anaplastic large cell lymphoma (ALCL) is composed of large, frequently bizarre, cells of T- or null-cell phenotype that show a preferential sinusoidal growth pattern and consistent CD30 positivity. Whether these tumors represent a single entity or several, and what the exact cell origin, is controversial. Recently, granzyme B, a cytotoxic granule component, was reported in a small percentage of ALCL, suggesting that some cases may originate from cytotoxic lymphocytes. To further investigate this possibility, we performed an immunohistochemical study of 33 ALCLs of T- and null-cell type, using monoclonal antibodies to cytotoxic cell-associated antigens, including CD8, CD56, CD57, and the cytotoxic granular proteins perforin and TIA-1. In addition, CD4 expression was also evaluated. ALCL cases included 27 classical systemic forms and variants, 3 primary cutaneous (PC) forms, and 3 acquired immunodeficiency syndrome-associated forms. Cytotoxic antigen expression was also studied in 51 cases of Hodgkin's disease (HD) and 17 large B-cell lymphomas (LBCLs) with anaplastic cytomorphology and/ or CD30 positivity. We found that 76% of ALCLs, representing all subtypes except the PC forms, expressed either TIA-1, perforin, or both proteins. Expression of TIA-1 and perforin were highly correlated (P < .001). On the basis of their immunophenotypic profiles, several subtypes of cytotoxic antigen positive and negative ALCL could be recognized. Fifty-five percent of ALCLs (18 of 33) displayed an immunophenotypic profile consistent with cytotoxic T cells. Six cases expressed cytotoxic granular proteins in the absence of lineage specific markers, and one case expressed both T-cell- and natural killer cell-like markers. These 7 cases (21%) were placed into a phenotypic category of cytotoxic lymphocytes of unspecified subtype. Twenty-four percent (8 cases) of ALCLs were cytotoxic granule protein negative. All but one of these displayed a T-cell phenotype. Cytotoxic granule protein expression did not correlate with the presence of the NPM-ALK fusion transcript. Only 10% of the 51 HD cases were found to be TIA-1+, and none expressed perforin. Cytotoxic antigen expression was absent in LBCL. The expression of cytotoxic granule proteins in the majority of ALCL implies a cytotoxic lymphocyte phenotype and suggests that most cases originate from lymphocytes with cytotoxic potential. Furthermore, the demonstration of cytotoxic cell related proteins may be a useful addition to the current panel of antibodies used to distinguish ALCL, HD, and anaplastic LBCL.
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PMID:Cytotoxic cell antigen expression in anaplastic large cell lymphomas of T- and null-cell type and Hodgkin's disease: evidence for distinct cellular origin. 902 30

Hepatocyte growth factor (HGF)/scatter factor (SF) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogene (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HGF/ SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34+ cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET-, c-MET expression was induced by PMA, ConA, HGF/ SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non-Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET+ B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by beta 1-integrins alpha 4 beta 1 (VLA4) and alpha 5 beta 1 (VLA5) since blocking antibodies against beta 1- (CD29), alpha 4-(CD49d), or alpha 5- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET+ B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and invasion assays HGF/SF had no effect on c-MET- cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET+ B-lymphoma cells to FN and CN, mediated via beta 1-integrins alpha 4 beta 1 and alpha 5 beta 1, and furthermore promoted migration and invasion.
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PMID:Hepatocyte growth factor/scatter factor promotes adhesion of lymphoma cells to extracellular matrix molecules via alpha 4 beta 1 and alpha 5 beta 1 integrins. 902 31

The t(2;5)(p23;q35) translocation, associated with anaplastic large-cell lymphoma (ALCL), results in the production of the nucleolar protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) protein. This report describes an immunocytochemical study of the distribution of ALK and NPM-ALK proteins using a new monoclonal antibody, ALK1, that recognizes a formalin resistant epitope in both the 80-kD NPM-ALK chimeric and the 200-kD normal human ALK proteins. Cytoplasmic and nuclear labeling was seen in the t(2;5)+ SU-DHL-1 and Karpas 299 cell lines. Normal ALK protein expression was restricted to the central nervous system (in scattered neurons, glial cells, and endothelial cells). Two hundred and thirty-nine cases of lymphoma and 80 nonhematopoietic tumors were immunostained. Antibody ALK1 labeled 53.4% (39 of 73 cases) of CD30+ ALCL. A case of ALCL with a t(1;2) translocation was ALK1+. Three cases of CD30- ALCL with prominent nucleoli showed a unique pattern of coarse granular cytoplasmic labeling. All other tumors, including Hodgkin's disease and lymphomatoid papulosis, were ALK1-. These results indicate that reliable immunostaining of routine biopsy material for NPM-ALK and ALK proteins is feasible. Such analysis is of diagnostic importance, especially because t(2;5)+ ALCL cases have a good prognosis with appropriate treatment.
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PMID:Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. 902 63

The non-Hodgkin's lymphoma (NHL) subset commonly referred to as large cell lymphoma (LCL) has historically been characterized by it's marked cytological, immunological, and clinical heterogeneity. One potential defining feature of these lymphomas, the t(2;5)(p23;q35), occurs in 25% to 30% of anaplastic LCLs and is also found in cases with diffuse large cell or immunoblastic morphology. We recently identified nucleophosmin (NPM) and anaplastic lymphoma kinase (ALK) as the genes on chromosomes 5 and 2, respectively, that are juxtaposed by this translocation. To provide a complementary approach to the use of classical cytogenetics or polymerase chain reaction-based methods for the detection of this abnormality, we have developed a two-color fluorescent in situ hybridization (FISH) assay for the t(2;5) that may be used for the analysis of both interphase nuclei and metaphase chromosomes. Three overlapping chromosome 5 cosmid clones located immediately centromeric to the NPM gene locus and an ALK P1 clone located telomeric to the chromosome 2 breakpoint were labeled with digoxigenin or biotin, respectively, and used to visualize the derivative chromosome 5 produced by the t(2;5), evident as juxtaposed or overlapping red and green fluorescent signals. This NPM-ALK FISH assay was initially validated by analysis of a series of cytogenetically characterized cell lines, with the presence of the der(5) chromosome showed specifically only in those lines known to contain the t(2;5). The assay was then applied in a blinded fashion to a series of eight cytogenetically t(2;5)-positive clinical specimens and seven known t(2;5)-negative cases, including three NHL and four Hodgkin's disease biopsy samples. Whereas the t(2;5)-negative cases were negative by FISH, all eight t(2;5)-positive cases were positive. One additional case, initially thought to be positive for the translocation by cytogenetics, was proven to not be a classic t(2;5) by interphase and metaphase FISH. These data indicate that the FISH assay described is a highly specific and rapid test that should prove to be a useful adjunct to the currently available methods for detection of the t(2;5).
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PMID:Detection of the t(2;5)(p23;q35) and NPM-ALK fusion in non-Hodgkin's lymphoma by two-color fluorescence in situ hybridization. 905 50

Anaplastic large cell lymphoma (ALCL) is a heterogeneous group of diseases by morphology, phenotype, genotype, and clinical presentation. Using a new monoclonal antibody (ALK1) that recognizes the native anaplastic lymphoma kinase (ALK) protein as well as the fusion product of the t(2;5)(p23;q35), nucleophosmin (NPM)/ALK, we investigated for ALK expression cases diagnosed as ALCL as well as lympho-proliferative disorders possessing overlapping features with ALCL. Thirteen cases showed cytoplasmic staining of the neoplastic cells. These cases were characterized by a fairly uniform morphology and occurred in children and young adults as a systemic disease. All other cases comprising T or null ALCL (17 cases), B ALCL (8 cases), Hodgkin's disease (HD) (15 cases), HD-like ALCL (23 cases), and lymphomatoid papulosis (9 cases), were negative for ALK expression. Translocation t(2;5)(p23;q35) was found by classical cytogenetics or interphase fluorescence in situ hybridization in 8 of the ALK1-positive cases and by reverse transcription-polymerase chain reaction in 1 other case. Two additional ALK1-positive cases with an abnormal karyotype, but without t(2;5)(p23;q35), showed by fluorescence in situ hybridization analysis a cryptic NPM/ALK gene fusion caused by an insertion of ALK near NPM in one case and a translocation of ALK to 2q35 as a result of an indiscernible inv(2)(p23q35) in the other. The latter variant translocation points to a localization of an unknown gene at 2q35 that, like NPM, might deregulate ALK and be involved in the pathogenesis of ALCL. In summary, immunohistochemistry with ALK1 antibody allows the identification of a distinct subgroup within the ALCL of T or null phenotype that is associated with 2p23 abnormalities and lacks the marked histological pleomorphism described in ALCL in general. Whereas immunostaining is the most sensitive method to identify this group, it does not help to additionally clarify the relationship among ALCL, HD, and HD-like ALCL.
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PMID:The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements. 925 Jan 48

In 20%-50% of the advanced cutaneous T-cell lymphomas (CTCL), malignant T cells undergo large cell transformation (LCT). The malignant T cells of LCT in CTCL can share morphologic and immunophenotypic similarities with CD30 (Ki-1)-positive anaplastic large cell lymphoma (ALCL), suggesting a common mechanism of pathogenesis. The t(2;5) (p23;q35) translocation, resulting in the fusion of the nucleophosmin (NPM) gene and the anaplastic lymphoma kinase (ALK) gene, is associated with primary CD30+ ALCL. To determine whether acquisition of this chromosomal translocation is involved in the pathogenesis of LCT in CTCL, we examined 12 tumor samples from 9 CTCL patients, including 8 with LCT-CTCL and one with concurrent CTCL and Hodgkin's disease, for the presence of the t(2;5) translocation. Numerous CD30+ large cells were present in 4 LCT-CTCL consistent with secondary CD30+ ALCL; CD30 was expressed by <10% of the large cells in another case and was negative in the other 3 lymphomas. Using primers spanning the NPM/ALK fusion junction, PCR amplification following reverse transcription (RT) of mRNA failed to show the products of NPM/ALK fusion in all samples tested. Thus, the t(2;5) (p23;q35) translocation does not appear to be involved in the molecular pathogenesis of LCT in CTCL, including CD30+ cases.
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PMID:The pathogenesis of large cell transformation in cutaneous T-cell lymphoma is not associated with t(2;5)(p23;q35) chromosomal translocation. 927 57

Ionizing radiation is a well-known risk factor of cancer development, but the mechanism of radiation induced carcinogenesis is not clear. Chromosomal rearrangements induced by radiation most likely are one of the principal genetic alterations resulting in malignant transformation. The chimeric BCR-ABL associated with chronic myelogenous leukemia (CML) and H4-RET oncogenes associated with thyroid papillary carcinoma are the result of a translocation and inversion, respectively. In vitro studies showed these genes were induced by high-doses of X-irradiation in cell lines. Studies also show that therapeutic external X-ray doses as high as 60 Gy for treatment of various childhood cancers including Hodgkin's disease significantly increase the risk of thyroid cancer. Therefore, we examined the induction and persistence of these chimeric genes in human thyroid tissues transplanted in scid mice after 50 Gy exposure as a function of time for 2 months to elucidate the early events of thyroid carcinogenesis. The H4-RET genes were detected on day 2 and throughout the 2 month period. On the other hand, BCR-ABL genes were detected on day 2 and were undetectable subsequently. These results suggest that ionizing radiation causes various oncogene activations, but cells with only specific gene alteration uniquely associated with thyroid carcinogenesis are selectively retained demonstrating one of the early events in the beginnings of radiation carcinogenesis in human thyroid tissues.
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PMID:Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. 933 21

Approximately 5% to 10% of all non-Hodgkin's lymphomas contain a t(2;5)(p23;q35) chromosomal rearrangement, which we have previously shown results in the generation of the fusion protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). To assess the transforming potential of NPM-ALK in an animal model, we infected 5-fluorouracil-treated murine bone marrow using retroviral stocks and transplanted this infected marrow into lethally irradiated BALB/cByJ mice. Male mice were transplanted with bone marrow from female donors at 10 weeks of age, with 7 of the animals receiving marrow infected with a retroviral construct, pSR alphaMSVtkneo-NPM-ALK, that contains the human NPM-ALK cDNA, and 4 serving as a control group, receiving "empty" pSR alphaMSVtkneo-infected marrow. Whereas all mice in the control group were alive and well up to 11 months after transplantation, 4 of the 7 mice transplanted with marrow containing the NPM-ALK construct developed lymphoma within 4 to 6 months. Tumors arose in the mesenteric lymph nodes, with metastases to the lungs, kidneys, liver, spleen, and the paraspinal area. When cells from the tumors and bone marrow were transplanted into sublethally irradiated secondary recipients, 10 of these 13 mice developed tumors within 9 months. Immunoblot analysis of cell lysates using an ALK polyclonal antibody showed NPM-ALK expression in all tumors examined. Histologically, the tumors were composed of a uniform population of large immunoblastic cells with basophilic cytoplasm, centrally placed nuclei, and distinct nucleoli. Genotypic analysis showed that the tumors were B-lineage and clonal, with rearrangements of the Ig heavy- and kappa light-chain loci and no rearrangements of the T-cell receptor beta locus. Immunocytochemical studies confirmed the presence of IgM heavy chains and kappa light chains within the tumor cells. Thus, in this retroviral gene transfer model, NPM-ALK expression in mice causes B-lineage large-cell lymphoma, suggesting a direct causative role for this activated fusion tyrosine kinase in human lymphoma.
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PMID:Retrovirus-mediated gene transfer of NPM-ALK causes lymphoid malignancy in mice. 937 69


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