UMLS:C0019829 - FACTA Search

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Query: UMLS:C0019829 (Hodgkin's disease)
30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifty-six cases of anaplastic large cell lymphoma (ALCL), 23 cases of Hodgkin's disease, and 16 cases of diffuse large cell lymphoma were investigated for the t(2;5)(p23;q35) translocation. The translocation was detected by using cytogenetic analysis, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry with P80 antibody directed against the kinase domain of anaplastic lymphoma kinase (ALK) of the chimeric NPM/ALK protein. In all but three cases of ALCL, we found an agreement between cytogenetic analysis, RT-PCR, and P80 staining. However, in one case, the t(2;5) translocation was detected with cytogenetic analysis, but RT-PCR and P80 staining were found to be negative. Conversely, in another case the karyotype was normal, but the hybrid mRNA and P80 staining were found to be positive. In one case, malignant cells showed a translocation involving chromosomes 1q25 and 2p23 and were strongly positive for P80 staining. Such a result could be expected because P80 antibody detects the kinase domaine of the ALK protein encoded by chromosome 2p23. Overall 73.2% (41 of 56) of cases were found to be positive. However, the highest percentage (23 of 26 cases; 88.5%) of P80 positive cases was found in children compared with 60% (18 of 30 cases) in adult ALCL (P < .05). In Hodgkin's disease, Reed-Sternberg cells were found to be clearly negative by RT-PCR and with P80 antibody. The latter results suggest that Hodgkin's disease and t(2;5)-positive ALCL are distinct biological entities and that the demonstration of the t(2;5) translocation is of diagnostic importance in differentiating these two entities. The results of the present study indicate that immunohistochemistry with P80 antibody is a reliable method for detecting NPM/ALK chimeric protein.
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PMID:High incidence of the t(2;5)(p23;q35) translocation in anaplastic large cell lymphoma and its lack of detection in Hodgkin's disease. Comparison of cytogenetic analysis, reverse transcriptase-polymerase chain reaction, and P-80 immunostaining. 854 53

A recurrent, reciprocal balanced translocation, t(2;5) (p23;q35), has been recognized in CD30+ anaplastic large-cell lymphomas (ALCL), a newly recognized subtype comprising approximately 5% of all non-Hodgkin's lymphoma (NHL). This translocation creates a novel fusion protein, NPM-ALK, which has transforming properties in vitro and can cause large-cell lymphoma in vivo when transfected into murine bone marrow. Multiple techniques including reverse transcriptase-polymerase chain reaction (RT-PCR) amplification of NPM-ALK fusion transcripts, genomic DNA-PCR, RNA in situ hybridization, and fluorescence in situ hybridization (FISH) of metaphase chromosomes and interphase nuclei, and immunohistochemical detection of the 80 kilodalton protein (p80) derived from the NPM-ALK fusion have enabled surveys of normal and lymphoma tissues for evidence of the translocation. These studies suggest that expression of ALK protein, a novel orphan receptor tyrosine kinase, is normally confined to the nervous system. In lymphoma, NPM-ALK expression is most often seen in young patients with the monomorphic or small-cell variant of ALCL who present with advanced stage disease and have tumors with a CD30+, T- or null-cell phenotype. It is less frequently detected in older patients and in ALCL of pleomorphic histology. In addition, expression of NPM-ALK has been found in occasional CD30 negative B-cell lymphomas with diffuse large cell or immunoblastic histology. NPM-ALK is rarely, if ever, detected in Hodgkin's disease or secondary ALCL. Although initially found in primary nodal ALCL, recent studies suggest that NPM-ALK expression may occur in lymphoma at extranodal sites, including the skin; it remains controversial, however, whether CD30+ primary cutaneous lymphoma and its benign counterpart, lymphomatoid papulosis (LyP), express NPM-ALK in some cases. A retrospective study has suggested that expression of NPM-ALK is associated with a better overall 5-year survival; these results must be confirmed in prospective studies of patients with uniform staging and therapy to more fully understand the clinical significance of the t(2;5) and its novel chimeric protein, NPM-ALK.
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PMID:The t(2;5) in human lymphomas. 968 23

The data of a closed phase I/II trial in patients with resistant Hodgkin's lymphoma indicate promising results using a chemically linked anti-CD25 ricin-A immunotoxin (IT) (RFT5-SMPT-dgA). This IT is based on the high-affinity moab RFT5. Since recombinant DNA technology permits the readier production of large amounts of ITs, we constructed a new RFT5-based fusion toxin [RFT5(scFv)-ETA']. We isolated mRNA from the hybridoma cell line RFT5, synthesized first strand cDNA and performed RT-PCR. Amplified coding regions of the light and heavy chain variable domains were joined together with a synthetic (Gly4-Ser)3 linker. The resulting single chain variable fragment (scFv) was fused to a modified Pseudomonas aeruginosa exotoxin A (ETA') lacking its cell-binding domain I. After IPTG-induced expression in Escherichia coli, the 70 kDa His-tagged fusion protein [RFT5(scFv)-ETA'] was isolated by osmotic shock and sonication under denaturing conditions. The recombinant toxin was purified on a Ni2+-NTA chelating sepharose and eluted with 250 mM imidazole. Pooled protein was renatured, dialyzed and concentrated by precipitation. Binding properties of RFT5(scFv)-ETA' were assessed on the CD25-expressing cell line L540cy by ELISA, immunohistochemistry and FACS analysis. CD25-specific binding was confirmed by immunoprecipitation experiments with recombinant human IL-2 receptor alpha. The in vitro toxicity of the chimeric protein was tested on the Hodgkin-derived cell lines L540cy, L428, L1236, a monocyte cell line U937 and a Burkitt lymphoma cell line BL38. RFT5(scFv)-ETA' inhibited protein biosynthesis of L540cy and L428 cells by 50% at concentrations (IC50) of 18 and 12 ng/ml, respectively. CD25-specific toxicity was confirmed by competitive toxicity assays. These data confirm for the first time binding specificity and toxicity of a recombinant anti-CD25 immunotoxin, against Hodgkin-derived cell lines; its applicability on Hodgkin's lymphoma needs yet to be evaluated in vivo.
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PMID:Construction and in vitro evaluation of RFT5(scFv)-ETA', a new recombinant single-chain immunotoxin with specific cytotoxicity toward CD25+ Hodgkin-derived cell lines. 985 27

The heterogenous group of anaplastic large cell lymphomas (ALCLs) is characterized by expression of the Ki-1/CD30 antigen, a member of the tumor necrosis factor receptor superfamily. About 40 to 50% of cases diagnosed as ALCL contain a specific chromosomal rearrangement, t(2;5)(p23;q35), resulting in expression of the chimeric tyrosine kinase NPM-ALK. As NPM-ALK-positive lymphomas define a distinct subtype within the group of ALCL, the chimeric protein might be responsible for certain pathogenetic and clinicopathologic characteristics. To better elucidate the function of NPM-ALK, we investigated a possible mechanism for regulation of its activity. We demonstrate that NPM-ALK specifically binds to the intracellular domain of the cytokine receptor CD30. In vitro binding assays revealed that the ALK portion of NPM-ALK mediates interaction of the two proteins. Stimulation of the CD30 receptor by cross-linking with immobilized anti-CD30 antibody results in complete growth inhibition of Karpas 299, an NPM-ALK-positive ALCL cell line, but does not alter proliferation of HDLM-2, a Hodgkin's lymphoma-derived cell line lacking t(2;5). Western blot analysis of coimmunoprecipitated CD30 and NPM-ALK proteins from stimulated Karpas 299 cells showed that the interaction of the proteins is not modified by stimulation. Activation of CD30 neither enhanced NPM-ALK activity measured by autophosphorylation of the chimeric tyrosine kinase nor phosphorylation of phospholipase C-gamma, an NPM-ALK substrate. We conclude that NPM-ALK is not stimulated by CD30 activation, but exists as a constitutively hyperactivated protein. Interaction with CD30 may extend the subcellular localization of NPM-ALK to the microenvironment of membrane-associated proteins.
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PMID:The tyrosine kinase NPM-ALK, associated with anaplastic large cell lymphoma, binds the intracellular domain of the surface receptor CD30 but is not activated by CD30 stimulation. 1064 97

The non-Hodgkin lymphoma (NHL) subtype anaplastic large-cell lymphoma (ALCL) is frequently associated with a t(2;5)(p23;q35) that results in the fusion of the ubiquitously expressed nucleophosmin (NPM) gene at 5q35 to the anaplastic lymphoma kinase (ALK) gene at 2p23, which is not normally expressed in hematopoietic tissues. Approximately 20% of ALCLs that express ALK do not contain the t(2;5), suggesting that other genetic abnormalities can result in aberrant ALK expression. Here we report the molecular characterization of an alternative genetic means of ALK activation, the inv(2)(p23q35). This recurrent abnormality produces a fusion of the amino-terminus of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC), a bifunctional homodimeric enzyme that catalyzes the penultimate and final steps of de novo purine nucleotide biosynthesis, with the intracellular portion of the ALK receptor tyrosine kinase. RT-PCR analysis of 5 ALCL tumors that contained the inv(2) revealed identical ATIC-ALK fusion cDNA junctions in all of the cases. Transient expression studies show that the ATIC-ALK fusion transcript directs the synthesis of an approximately 87-kd chimeric protein that is localized to the cytoplasm, in contrast to NPM-ALK, which typically exhibits a cytoplasmic and nuclear subcellular distribution. ATIC-ALK was constitutively tyrosine phosphorylated and could convert the IL-3-dependent murine hematopoietic cell line BaF3 to cytokine-independent growth. Our studies demonstrate an alternative mechanism for ALK involvement in the genesis of NHL and suggest that ATIC-ALK activation results from ATIC-mediated homodimerization. In addition, expected decreases in ATIC enzymatic function in ATIC-ALK-containing lymphomas may render these tumors more sensitive to antifolate drugs such as methotrexate. (Blood. 2000;95:2144-2149)
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PMID:Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. 1070 87

A number of different immunotoxins composed of cell-specific targeting structures coupled to plant or bacterial toxins have increasingly been evaluated for immunotherapy. Because these foreign proteins are highly immunogenic in humans, we have developed a new CD30 ligand-based fusion toxin (Ang-CD30L) using the human RNase angiogenin. The completely human fusion gene was inserted into a pET-based expression plasmid. Transformed Escherichia coli BL21(DE3) were grown under osmotic stress conditions in the presence of compatible solutes. After isopropyl beta-D-thiogalactoside induction, the M(r) 37,000 His(10)-tagged Ang-CD30L was directed into the periplasmic space and functionally purified by a combination of metal ion affinity followed by enterokinase cleavage of the His(10)-Tag and molecular size chromatography. The characteristics of the recombinant protein were assessed by ELISA, flow cytometry, and toxicity assays showing specific activity against CD30(+) Hodgkin-derived cells. Specific binding activity of Ang-CD30L was verified by competition with anti-CD30 monoclonal antibody Ki-4 and commercially available CD30L-CD8 chimeric protein. Ang-CD30L showed RNase activity in vitro. The human recombinant immunotoxin showed significant toxicity toward several CD30-positive cell lines (HDLM-2, L1236, KM-H2, and L540Cy) and exhibited highest cytotoxicity against L540 cells (IC(50) = 8 ng/ml) as determined by cell proliferation assays. CD30 specificity was confirmed by competitive toxicity assays. This is the first report on the specific cytotoxicity of a recombinant completely human fusion toxin with possibly largely reduced immunogenicity for the treatment of CD30-positive malignancies.
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PMID:Human angiogenin fused to human CD30 ligand (Ang-CD30L) exhibits specific cytotoxicity against CD30-positive lymphoma. 1175 93

CD30 is expressed on Hodgkin's Reed-Sternberg (H-RS) cells, the tumor cells in Hodgkin's disease. Increased levels of serum CD30 are observed in Hodgkin's disease patients and are a good marker for predicting a poor prognosis and a poor response to therapy. In this study, we addressed the effect of CD30 on T cells. We showed that CD30, either as a membranous protein on H-RS cells and Chinese hamster ovary cells or as a plate-bound chimeric protein, inhibited T-cell proliferation. Anti-CD3-stimulated T cells in the presence of CD30 failed to increase tritium uptake and failed to express CD25 and CD26 and to produce interleukin 2. The inhibition of T-cell proliferation was, however, reversed with addition of exogenous interleukin 2 or pretreatment of H-RS cells with anti-CD30. Inability of T cells to express CD25 and CD26 in cocultures with H-RS cells or a plate-bound CD30 chimeric protein is in accordance with the results of immunohistochemistry on disease-involved tissues. We conclude that H-RS cells are able to inhibit the proliferation and activation of T cells through CD30-related interaction. The outcome of CD30-related interaction is an ineffective antitumor immunity, which is clearly in favor of the growth and survival of the tumor cells.
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PMID:CD30 is involved in inhibition of T-cell proliferation by Hodgkin's Reed-Sternberg cells. 1502 56

The BCL3 gene was initially discovered through its involvement in a recurring translocation, t(14;19)(q32;q13), which is found in some patients with B-cell chronic lymphocytic leukemia (B-CLL). The translocation leads to the juxtaposition of BCL3 to the immunoglobulin heavy chain gene locus, resulting in high-level expression of the BCL3 transcript. The Bcl-3 protein includes 7 tandem copies of the ankyrin repeat element in the central domain, a structure that is characteristic of the IkappaB family of inhibitors of the nuclear factor kappaB transcription factors. Anaplastic large cell lymphoma (ALCL) is a subtype of aggressive non-Hodgkin's lymphoma that is characterized by expression of CD30 and the NPM/ALK chimeric protein, which is generated by t(2;5)(p23;q35). We compared the gene expression profiles of ALCL with those of another CD30+ neoplasm, Hodgkin's disease (HD), and found that BCL3 is expressed at higher levels in ALCL than in HD. A comparison by real-time polymerase chain reaction assay revealed that t(2;5)+ ALCL expresses a high level of BCL3 messenger RNA relative to the levels expressed in other hematologic tumors, and the level in ALCL is comparable to or even higher than that in t(14;19)+ B-CLL. An immunohistochemical analysis of ALCL tumor tissues showed that the lymphoma cells exhibited strong nuclear staining by a monoclonal antibody against Bcl-3. We suggest that Bcl-3 sequestrates the (p50)2 homodimer to the nucleus and that the kappaB sites are occupied by the (p50)2/Bcl-3 ternary complex. Future studies should identify the relationships among the 3 independent molecules (ie, NPM/ALK, CD30, and Bcl-3) that are activated in t(2;5)+ ALCL.
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PMID:Reappraisal of BCL3 as a molecular marker of anaplastic large cell lymphoma. 1653 41

Anaplastic large cell lymphoma (ALCL) comprises a group of non-Hodgkin lymphomas characterized by the expression of the CD30/Ki-1 antigen. A subset of ALCL is characterized by chromosomal translocations involving the anaplastic lymphoma kinase (ALK) gene on chromosome 2. While the most common translocation is the t(2;5)(p23;q35) involving the nucleophosmin (NPM) gene on chromosome 5, up to 12 other translocations partners of the ALK gene have been identified. One of these is the t(1;2)(q25;p23) which results in the formation of the chimeric protein TPM3-ALK. While several of the signaling pathways induced by NPM-ALK have been elucidated, those involved in ALCLs harboring TPM3-ALK are largely unknown. In order to investigate the expression profiles of ALCLs carrying the NPM-ALK and TPM3-ALK fusions, we carried out cDNA microarray analysis of two ALCL tissue samples, one expressing the NPM-ALK fusion protein and the other the TPM3-ALK fusion protein. RNA was extracted from snap-frozen tissues, labeled with fluorescent dyes and analyzed using cDNAs microarray containing approximately 9,200 genes and expressed sequence tags (ESTs). Quantitative fluorescence RT-PCR was performed to validate the cDNA microarray data on nine selected gene targets. Our results show a significant overlap of genes deregulated in the NPM-ALK and TPM-ALK positive lymphomas. These deregulated genes are involved in diverse cellular functions, such as cell cycle regulation, apoptosis, proliferation, and adhesion. Interestingly, a subset of the genes was distinct in their expression pattern in the two types of lymphomas. More importantly, many genes that were not previously associated with ALK positive lymphomas were identified. Our results demonstrate the overlapping and unique transcriptional patterns associated with the NPM-ALK and TPM3-ALK fusions in ALCL.
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PMID:Analysis of gene expression profile of TPM3-ALK positive anaplastic large cell lymphoma reveals overlapping and unique patterns with that of NPM-ALK positive anaplastic large cell lymphoma. 1772 Feb 43

Remnants of ancient transposable elements (TEs) are abundant in mammalian genomes. These sequences harbor multiple regulatory motifs and hence are capable of influencing expression of host genes. In response to environmental changes, TEs are known to be released from epigenetic repression and to become transcriptionally active. Such activation could also lead to lineage-inappropriate activation of oncogenes, as one study described in Hodgkin lymphoma. However, little further evidence for this mechanism in other cancers has been reported. Here, we reanalyzed whole transcriptome data from a large cohort of patients with diffuse large B-cell lymphoma (DLBCL) compared with normal B-cell centroblasts to detect genes ectopically expressed through activation of TE promoters. We have identified 98 such TE-gene chimeric transcripts that were exclusively expressed in primary DLBCL cases and confirmed several in DLBCL-derived cell lines. We further characterized a TE-gene chimeric transcript involving a fatty acid-binding protein gene (LTR2-FABP7), normally expressed in brain, that was ectopically expressed in a subset of DLBCL patients through the use of an endogenous retroviral LTR promoter of the LTR2 family. The LTR2-FABP7 chimeric transcript encodes a novel chimeric isoform of the protein with characteristics distinct from native FABP7. In vitro studies reveal a dependency for DLBCL cell line proliferation and growth on LTR2-FABP7 chimeric protein expression. Taken together, these data demonstrate the significance of TEs as regulators of aberrant gene expression in cancer and suggest that LTR2-FABP7 may contribute to the pathogenesis of DLBCL in a subgroup of patients.
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PMID:Distinct isoform of FABP7 revealed by screening for retroelement-activated genes in diffuse large B-cell lymphoma. 2615 17

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