Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma characterized by the CD30+ large neoplastic cells and sometimes carries a t(2;5)(p23;q35). Recently, we found a novel hyperphosphorylated 80-kD protein tyrosine kinase, p80, in ALCLs with t(2;5). Subsequent cDNA cloning showed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene (Morris et al, Science 263:1281, 1994). Meanwhile, the clinicopathologic features of p80-carrying ALCLs have remained unclear. Paraffin sections of 105 cases of ALCL were immunostained using anti-p80 antibody, and 30 of them were shown to express p80. Clinicopathologic comparison between p80-positive and -negative ALCLs showed that p80-positive cases occurred in a far younger patient age group (16.2 +/- 12.9 years; p80-negative cases, 51.0 +/- 22.3 years; P < .0001) and the patients showed a far better 5-year survival rate (79.8%; p80-negative group, 32.9%; P < .01). These data showed that p80-positive ALCL is a distinct entity both clinically and pathogenetically and should be differentiated from p80-negative ALCL.
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PMID:Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. 765 22

We report on a 20-year-old woman who developed a pelvic small round cell tumor with lung metastases 8 years after diagnosis and successful treatment for Ki-1-positive anaplastic large cell lymphoma (Ki-1+ ALCL) with histiocytic differentiation. Molecular genetic detection of EWS/FLI-1 fusion gene expression in the second tumor by RT-PCR unambiguously confirmed the histopathologic diagnosis of Ewing tumor (ET), whereas no evidence for the presence of this specific gene rearrangement was obtained in a retrospective analysis of the lymphoma tissue. In contrast, expression of a NPM/ALK chimeric gene was observed which was absent in the ET. Moreover, the lymphoma contained a monoallelic D delta 2-D delta 3 T-cell receptor gene rearrangement which was also absent in the ET. Thus, our histopathologic, immunohistochemical, and, in particular, molecular genetic studies support the notion that these tumors were most probably pathogenetically unrelated. Since this is the first report describing such an association between a non-Hodgkin's lymphoma and ET and, since the latter has only rarely been observed as a second malignant neoplasm, it remains a matter of speculation whether in this patient ET developed as a therapy-related secondary neoplasm or independently from the lymphoma as a consequence of either genetic tumor predisposition or mere accidental coincidence.
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PMID:Ewing tumor after treatment of Ki-1+ anaplastic large cell lymphoma. Therapy-associated secondary neoplasm or unrelated coincidence? 765 5

The t(2;5)(p23;q35) translocation was initially identified in cases of anaplastic large-cell lymphoma (ALCL) that expressed the Ki-1 (CD30) antigen. We have recently cloned this translocation and shown it to encode a chimeric product consisting of the N-terminal portion of a nonribosomal nucleolar phosphoprotein, nucleophosmin (NPM), from chromosome 5, fused to the kinase domain of a novel transmembrane tyrosine-specific protein kinase, anaplastic lymphoma kinase (ALK), from chromosome 2. To better define the spectrum of lymphomas that contain this translocation, we have analyzed 70 cases of non-Hodgkin's lymphoma (NHL) for expression of the t(2;5)-derived NPM/ALK chimeric message by reverse transcriptase-polymerase chain reaction (RT-PCR). Using a previously described set of oligonucleotide primers, NPM/ALK chimeric transcripts were detected in 21 of 22 cases that contained the t(2;5) by cytogenetic analysis and in 10 of 48 cases that either lacked evidence of the t(2;5) or had unsuccessful cytogenetics. In all but 1 case, the NPM/ALK PCR products were of identical size and sequence, suggesting that the genomic chromosome breaks are clustered in a single intron in both NPM and ALK. The NPM/ALK-expressing cases were not confined to NHLs with anaplastic morphology and included 15 ALCLs, 6 immunoblastic lymphomas, and 10 diffuse large-cell lymphomas. Moreover, only slightly greater than half of the cases with anaplastic morphology and 59% of CD30-expressing cases were NPM/ALK positive. Thus, neither anaplastic morphology nor the expression of CD30 accurately predicted the presence of this molecular genetic subtype of lymphoma.
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PMID:Molecular detection of the (2;5) translocation of non-Hodgkin's lymphoma by reverse transcriptase-polymerase chain reaction. 778 Jan 28

The CD30+ anaplastic large cell lymphoma (ALCL) represents a new lymphoma entity thought to be related to Hodgkin'S disease (HD), but displaying also its own unique features. Cytogenetic studies of ALCL have demonstrated the presence of a (2;5)(p23;q35) translocation in a substantial number of these cases. Recently, the t(2;5) has been cloned and described to represent fusion of the NPM gene with the ALK gene on chromosome 5. To better define the spectrum of lymphomas containing this abnormality we have analyzed 50 continuous human cell lines established from various types of non-Hodgkin's lymphoma, ALCL and HD. In a first step, the expression of the NPM-ALK fusion gene was examined by reverse transcriptase-polymerase chain reaction (RT-PCR). In a second step, the t(2;5)-carrying cells were tested for the translation of functional chimeric mRNA into a fusion protein by immuno-staining of single cells with a polyclonal antibody. The NPM-ALK fusion transcript and the p80 protein were detected in eight of nine ALCL cell lines. We were unable to find PCR evidence for the t(2;5) in any of the non-ALCL cell lines including other CD30+ cell lines. As all seven bona fide HD cell lines were NPM-ALK-negative, these results do not support the notion that the t(2;5) represents a chromosomal aberration common to both ALCL and HD.
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PMID:The (2;5)(p23;q35) translocation in cell lines derived from malignant lymphomas: absence of t(2;5) in Hodgkin-analogous cell lines. 855 20

The classification of malignant lymphoma has been based on morphological and immunophenotypical findings for a long time. Recently, as chromosomal and genomic abnormalities which closely relate to the specific subtypes of lymphoma are revealed, these factors becoming much more important in the evaluation of differences in clinicopathological features of the various lymphoma subtypes. Anaplastic large cell lymphoma (ALCL) is a subtype of non-Hodgkin's lymphoma (NHL) involving large CD30+ neoplastic cells, which occasionally carries the chromosomal translocation t(2;5)(p23;q35). We have recently found a novel hyperphosphorylated 80-kDa protein tyrosine kinase, p80 which is expressed specifically in human ALCLs with this translocation. Subsequent cDNA cloning showed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene. In order to clarify the clinicopathologic features of p80-carrying ALCLs, we developed an anti-p80 polyclonal antibody, which immunoprecipitated, immunoblotted and immunostained p80 specifically. When paraffin sections of 105 cases of ALCL were stained using the anti-p80 antibody, 30 were shown to be p80 positive Clinicopathological comparison between p80-positive and p80-negative ALCLs revealed that the p80-positive cases occurred in a much younger patient age group and that the patients showed a far better 5-year survival rate. These data suggest that p80-positive ALCL is a distinct entity and should be differentiated from p80-negative ALCL.
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PMID:The clinicopathological features of anaplastic large cell lymphomas expressing p80NPM/ALK. 902 82

CD30(+)-anaplastic large cell lymphoma (ALCL) is a distinct clinicopathologic entity of non-Hodgkin's lymphoma that is immunologically heterogeneous. Bimodal age distribution, a nonrandom chromosome abnormality [t(2;5)(p23;q35)] that produces a chimeric protein p80npm/alk, and a variable (5-47%) association with Epstein-Barr virus (EBV) have been reported. We reviewed 36 cases of ALCL (19 were children < 20 yr and 17 were adults) by focusing on the presence or absence of p80npm/alk protein and EBV. Immunophenotyping studies were performed on frozen and/or paraffin sections before initiation of chemotherapy. The p80 protein was immunohistochemically examined, and EBV-encoded RNA transcripts were detected by in situ hybridization. Among 19 cases in children, 13 cases had a T-cell and 6 cases had a null-cell phenotype. p80 Was detected in 16 (84.2%) of 19 cases in children and 3 (17.6%) of 17 cases in adults. All of the 19 cases of p80-positive ALCL were positive for epithelial membrane antigen, regardless of age. EBV genome was not detected in any of 19 cases in children and in only 2 of 15 cases in adults. ALCL in childhood seems to constitute a homogeneous entity characterized by expression of p80 and absence of EBV. The association of EBV is also infrequent in adult ALCL among Japanese patients.
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PMID:CD30-positive anaplastic large cell lymphoma in childhood: expression of p80npm/alk and absence of Epstein-Barr virus. 907 28

Cytogenetic investigations were performed in a case of a nodal malignant non-Hodgkin's lymphoma. Histopathological analysis from an involved lymph node as well as from a skin biopsy revealed a lymphohistiocytic variant of CD30-positive anaplastic large cell lymphoma (ALCL). A t(2;5)(p23;q35) chromosome translocation could be observed in all metaphases analysed. This finding was confirmed both by RT-PCR analysis of the NPM/ALK fusion protein and by positive staining with the p80(NPM/ALK) antibody. To the best of our knowledge, this is the first report of a t(2;5) documented by classic cytogenetics in the lymphohistiocytic variant of ALCL.
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PMID:A lymphohistiocytic variant of anaplastic large cell lymphoma with demonstration of the t(2;5)(p23;q35) chromosome translocation. 945 Aug 9

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R, TEL/TRKC(L), and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic leukemias and non-Hodgkin's lymphoma. FTK-transformed cells displayed drug resistance against the cytostatic drugs cisplatin and mitomycin C. These cells were not protected from drug-mediated DNA damage, implicating activation of the mechanisms preventing DNA damage-induced apoptosis. Various FTKs, except TEL/TRKC(L), can activate STAT5, which may be required to induce drug resistance. We show that STAT5 is essential for FTK-dependent upregulation of RAD51, which plays a central role in homology-dependent recombinational repair (HRR) of DNA double-strand breaks (DSBs). Elevated levels of Rad51 contributed to the induction of drug resistance and facilitation of the HRR in FTK-transformed cells. In addition, expression of antiapoptotic protein Bcl-xL was enhanced in cells transformed by the FTKs able to activate STAT5. Moreover, cells transformed by all examined FTKs displayed G(2)/M delay upon drug treatment. Individually, elevated levels of Rad51, Bcl-xL, or G(2)/M delay were responsible for induction of a modest drug resistance. Interestingly, combination of these three factors in nontransformed cells induced drug resistance of a magnitude similar to that observed in cells expressing FTKs activating STAT5. Thus, we postulate that RAD51-dependent facilitation of DSB repair, antiapoptotic activity of Bcl-xL, and delay in progression through the G(2)/M phase work in concert to induce drug resistance in FTK-positive leukemias and lymphomas.
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PMID:Fusion tyrosine kinases induce drug resistance by stimulation of homology-dependent recombination repair, prolongation of G(2)/M phase, and protection from apoptosis. 1202 32

Fusion tyrosine kinases (FTKs) such as BCR/ABL, TEL/ABL, TEL/JAK2, TEL/PDGF beta R and NPM/ALK arise from reciprocal chromosomal translocations and cause acute and chronic myelogenous leukemias and non-Hodgkin's lymphoma. Murine hematopoietic growth factor dependent BaF3 cells and cells transformed by FTK (BaF3-FTK) were used to investigate the role of FTKs in response to DNA damage. FTK-transformed cells displayed resistance to genotoxic treatment including gamma-radiation and cytostatic agents such as idarubicin and MNNG. More FTK-transformed cells survived genotoxic treatment and were able to proliferate in comparison to parental non-transformed cells. Similar or higher levels of DNA damage was detected in gamma-irradiated in BaF3-FTK cells in comparison to BaF3 parental cells. Idarubicin induced different amounts of DNA damage in various BaF3-FTK cells. All BaF3-FTK cells treated with MNNG displayed significantly more DNA damage in comparison to BaF3 cells. Despite the extent of genotoxic effect BaF3-FTK cells were often able to repair damaged DNA more efficiently that the non-transformed counterparts. Inhibition of BCR/ABL kinase activity by STI571 (Gleevec, inatinib mesylate) abrogated the resistance to genotoxic treatment and inhibited DNA repair mechanisms. We hypothesize that facilitation of the DNA repair in FTK-positive cells may contribute to their resistance to genotoxic treatment.
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PMID:Fusion oncogenic tyrosine kinases alter DNA damage and repair after genotoxic treatment: role in drug resistance? 1253 80

Activated double-stranded RNA (dsRNA)-dependent protein kinase PKR is a potent growth inhibitory protein that is primarily activated in virally infected cells, inducing them to die. We have recently shown that PKR can be selectively activated in cancer cells, by in situ generation of dsRNA following introduction of antisense RNA complementary to an RNA expressed specifically in the cancer cell. The feasibility of this approach was demonstrated using a glioblastoma line that overexpresses a truncated form of the EGFR. PKR and its signaling pathway are not restricted to a given cell line; therefore, in principle, this dsRNA killing approach can be applied to any cancer that expresses unique RNA sequences. Nonetheless, applying this approach to Karpas299 cells, from a T-cell non-Hodgkin's lymphoma that harbors the NPM/ALK translocation, did not result in cell death, implying that PKR signaling pathway is repressed in this cell line. Indeed, the phosphorylation of eIF2alpha by PKR was impaired in Karpas299 cells. Furthermore, levels of the cellular inhibitor p67 were elevated in these cells. Long antisense, as well as RNAi for p67, delivered into Karpas299 cells by adenoviruses, reduced p67 levels. The reduction in p67 levels led to increased phosphorylation of eIF2alpha, and an additive effect was achieved by coinfection with NPM/ALK-AS encoding adenoviruses. Infection with these adenoviruses, however, did not promote growth inhibition. These findings imply that anti-apoptotic mechanisms counteract PKR signaling in this T-cell non-Hodgkin's lymphoma.
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PMID:Activation of dsRNA dependent protein kinase PKR in Karpas299 does not lead to cell death. 1612 98


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