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Query: UMLS:C0079731 (B-cell lymphoma)
 16,671 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell proliferation, survival, and differentiation are carefully orchestrated processes during nephrogenesis that become aberrant during renal cyst formation. Signaling through focal adhesion kinase (FAK) impacts these processes, although its role during nephrogenesis requires further delineation. We previously demonstrated that phosphorylation of FAK and paxillin is not downregulated in cystic kidneys from B cell lymphoma/leukemia-2 (bcl-2) -/- mice. Here we examine whether FAK downstream signaling pathways are affected in these cystic kidneys. Cystic kidneys from bcl-2 -/- mice exhibited sustained phosphorylation of Src and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK, ERK1). However, similar levels of expression were noted for phosphorylated c-Jun NH(2)-terminal kinase, phosphatidylinositol-3-kinase, and its target protein kinase B/ATP-dependent tyrosine kinase in kidneys from postnatal day 20 bcl-2 +/+ and bcl-2 -/- mice. We also examined expression of the adapter protein Shc, implicated in growth and apoptosis. Expression of p66(Shc) decreases to low levels in postnatal kidneys, whereas p52/p46(Shc) was constitutively expressed during nephrogenesis. Shc expression was similar in normal and cystic kidneys. Therefore, sustained activation of MAPK/ERKs through the Src/FAK pathway may contribute to the hyperproliferation observed in cystic kidneys from bcl-2 -/- mice.
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PMID:Sustained activation of MAPK/ERKs signaling pathway in cystic kidneys from bcl-2 -/- mice. 1237 84

Callitrichine herpesvirus 3 (CalHV-3) was isolated from a B-cell lymphoma arising spontaneously in the New World primate Callithrix jacchus, the common marmoset. Partial genomic sequence analysis definitively identified CalHV-3 as a member of the Epstein-Barr virus (EBV)-related lymphocryptovirus (LCV) genus and extended the known host range of LCVs beyond humans and Old World nonhuman primates. We have now completed the first genomic sequence of an LCV infecting a New World primate by describing the unique short region, the major internal repeat, and a portion of the unique long region. This portion of the genome contains the putative latent origin of replication and 13 additional open reading frames (ORFs), 5 of which show no homology to any viral or cell genes. One of the novel genes, C5, is a positional homologue for the transformation-essential EBV gene EBNA-2. The marmoset LCV genome is also notable for the absence of viral interleukin-10 and small nonpolyadenylated RNA homologues. Marmoset LCV transcripts encoding putative latent infection nuclear proteins have a common leader sequence that is spliced from the major internal repeat in a manner similar to that of the EBV EBNA-LP, suggesting strong conservation of a common promoter and splicing of these latent infection mRNAs. An EBV LMP2A-like spliced transcript crossing the terminal repeats encodes a unique ORF, C7, with multiple transmembrane domains and tyrosine kinase phosphorylation sites functionally reminiscent of EBV LMP2A. However, the carboxy-terminal location of the candidate phosphotyrosine residues is more reminiscent of the Kaposi's sarcoma-associated herpesvirus K15 gene and provides potential evidence of an evolutionary transition from rhadinoviruses to lymphocryptoviruses. The unusual gene repertoire of the marmoset LCV differentiates ancestral viral genes likely present in an LCV progenitor from viral genes acquired later as primates and LCV coevolved, providing a defining point in the evolution of oncogenic LCVs.
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PMID:Complete genomic sequence of an Epstein-Barr virus-related herpesvirus naturally infecting a new world primate: a defining point in the evolution of oncogenic lymphocryptoviruses. 1241 47

The Fifteenth International Symposium of the Foundation for Promotion of Cancer Research entitled 'New Horizons in the Diagnosis and Treatment of Hematological Malignancies Based on Molecular Genetic Features' was held in Tokyo on January 15-17, 2002. Twenty-nine invited speakers, including 12 from abroad and 17 from Japan, presented the updated results of their research. After an overview of the classification of hematological malignancies, new findings on some disease entities based on novel immunophenotypic and molecular genetic features were presented. The results of gene expression profiling and BCL6 and C-MYC gene rearrangement in diffuse large B-cell lymphoma were presented and oncogenic mechanism of acute myeloid leukemia was discussed. In the treatment of non-Hodgkin's lymphoma and acute leukemia, the present consensus and future directions were discussed based on the results of multicenter trials in the USA and Japan. As a molecular targeting therapy, the remarkable effect of a BCR-ABL tyrosine kinase inhibitor, STI571, in chronic myeloid leukemia and gastrointestinal stromal tumor was presented. Thereafter, promising results of active immunotherapy, chimeric anti-CD20 monoclonal antibody, anti-CD20 radioimmunoconjugate and anti-CD22 immunotoxin for B-cell lymphoma were presented. Finally, recent advances in allogeneic hematopoietic stem cell transplantation were discussed, focusing on reduced-intensity preparative regimens. The recent advances in basic and clinical research on hematological malignancies would lead to further improvement in the prognosis and quality of life of patients suffering from leukemia or lymphoma.
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PMID:Report of the fifteenth international symposium of the foundation for promotion of cancer research: new horizons in the diagnosis and treatment of hematological malignancies based on molecular genetic features. 1241 6

Expression of ALK protein by lymphoid cells and the description of variant anaplastic lymphoma kinase (ALK) translocations have typically been restricted to cases of T-cell and null anaplastic large-cell lymphoma (ALCL). All such cases result from a novel fusion created by the ALK gene on chromosome 2p23 and NPM on 5q35 or other variant translocation partners. A rare variant of diffuse large B-cell lymphoma (DLBCL), originally described in 1997, was thought to overexpress full-length ALK in contrast to a chimeric protein characteristic of ALCL. However, full-length ALK protein lacks tyrosine kinase activity and thus the mechanism of oncogenesis has remained elusive. We describe 6 cases of ALK+ DLBCL characterized by a simple or complex t(2;17)(p23;q23) involving the clathrin gene (CLTC) at chromosome band 17q23 and the ALK gene at chromosome band 2p23. All cases were studied using fluorescence in situ hybridization (FISH), complemented in one case with standard cytogenetic analysis, multicolor karyotyping (M-FISH), and reverse transcriptase-polymerase chain reaction. These results clearly demonstrate that most cases of ALK+ DLBCL share the same mechanism of deregulated ALK expression. Moreover, these results demonstrate the presence of CLTC-ALK fusions in these tumors and extend the list of diseases associated with this genetic abnormality to include classical T-cell or null ALCL, ALK+ DLBCL, and inflammatory myofibroblastic tumors.
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PMID:ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases. 1276 27

In a previous study, we showed that the high level of protein tyrosine phosphorylation present in lymphomas containing an anaplastic lymphoma kinase (ALK) can be demonstrated in routinely processed paraffin tissue sections using immunolabelling techniques. In the present study we investigated whether oncogenic tyrosine kinase activation also occurs in other categories of lymphoma by staining 145 cases of lymphoma covering those tumours with a range of different subtypes including those with morphological similarity to ALK-positive anaplastic large cell lymphoma (ALCL). Twelve cases of the borderline malignant disorder lymphomatoid papulosis were also studied. Twenty seven of the 28 cases of ALK-positive ALCL showed the extensive cytoplasmic labelling for phosphotyrosine in the neoplastic cells. The remaining case containing moesin-ALK exhibited membrane-associated phosphotyrosine expression. There was no nuclear phosphotyrosine labelling in any of the ALK-positive ALCL, even though ALK was present within the cell nuclei in 23 of the tumours. Variable degrees of phosphotyrosine labelling, usually membrane-restricted, were observed in 7/40 cases of ALK-negative ALCL, 9/29 cases of diffuse large B-cell lymphoma, 3/6 cases of mediastinal B-cell lymphoma, 2/7 cases of Hodgkin's lymphoma, 3/6 cases of peripheral T-cell lymphomas unspecified, 4/6 cases of B-cell chronic lymphocytic leukaemia, 2/6 cases of follicular lymphomas and 2/12 cases of lymphomatoid papulosis studied. However none of these phosphotyrosine-positive cases showed the strong cytoplasmic labelling comparable to that seen in ALK-positive lymphoma. We conclude that activation of a tyrosine kinase is probably not a major oncogenic event in lymphomas other than ALK-positive ALCL.
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PMID:Tyrosine phosphorylation in human lymphomas. 1462 44

Controversy still exists over the response to therapy and prognosis of patients with primary mediastinal B-cell lymphoma (PMBL). Recent data from the International Extranodal Lymphoma Study Group (IELSG) suggest that a MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisone, bleomycin) chemotherapy regimen followed by radiotherapy may be a better induction strategy than other previously used treatments. Although the pathobiology of PMBL has been widely studied, its precise histology, phenotype, and molecular characteristics are still not clear. To date, phenotypic analysis has revealed the following phenotype: positivity for CD45 and CD20, but negativity for CD3, CD10, CD21, Class I/II major histocompatibility antigens, and a variety of other immunohistochemical markers. CD79a is generally detected, despite an absence of surface immunoglobulins (Igs). CD30 staining is observed in most cases, but is weaker and less homogeneous than in classic Hodgkin's lymphoma or anaplastic large cell lymphoma. BCL-2 protein is usually expressed but there are few data describing the expression of MUM1/IRF4, PAX5/BSAP, BCL-6, or the B-cell transcription factors BOB.1, Oct-2, and PU.1. Cytogenetic studies reveal gains in segments of chromosome 9p, including amplification of the REL proto-oncogene and the tyrosine kinase gene JAK2. Other molecular findings include: C-myc mutations or rearrangements, p53 mutations, IgV(H), gene mutations, and bcl-2 and mal over-expression. bcl-6 mutations and bcl-2 gene rearrangements are generally absent, suggesting that PMBL is of pre-germinal center (GC) origin. However, two recent reports show isotype-switched Ig genes with a high frequency of somatic hypermutations as well as variants in the 5' noncoding region of the bcl-6 gene. The IELSG collected 137 PMBL cases for extensive pathologic review. Histologically, the lymphomatous growth was predominantly diffuse with sclerosis that induced compartmentalized cell aggregation. It consisted of large cells with varying degrees of nuclear polymorphism and clear to basophilic cytoplasm. Molecular analysis was performed on 40 cases and showed novel findings. More than half of the cases displayed bcl-6 gene mutations, which usually occurred together with functioning somatic IgV(H) gene mutations, and BCL-6 and/or MUM1/IRF4 expression. The present study supports the concept that PBML is derived from activated GC or post-germinal center cells. However, it differs from other aggressive B-cell lymphomas in that it shows defective Ig production despite the expression of Oct-2, BOB.1, and PU.1 transcription factors, and a lack of IgV(H) gene crippling mutations.
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PMID:Pathobiology of primary mediastinal B-cell lymphoma. 1520 21

ZAP-70 is a tyrosine kinase expressed in normal T cells and NK cells. Expression of ZAP-70 has been associated with poor prognosis in B-cell chronic lymphocytic leukemia and might be a surrogate marker for immunoglobin heavy chain (IGH) mutational status in that disease. Little is known about ZAP-70 expression in other hematologic malignant neoplasms. We examined 446 specimens representing a range of hematopoietic malignant neoplasms for ZAP-70 expression by immunohistochemical analysis. As expected, most T cell-lineage disorders and a subset of small lymphocytic lymphomas were positive. IGH mutational status corresponded to ZAP-70 expression in a small subset of small lymphocytic lymphoma cases subjected to sequence analysis. Of note, however, ZAP-70 was expressed in a minority of other types of B-cell lymphomas, including precursor B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, mantle cell lymphoma, and very rare cases of classic Hodgkin lymphoma. Immunohistochemical analysis represents an alternative method for assessing ZAP-70 expression and reveals that other B-cell malignant neoplasms express ZAP-70.
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PMID:ZAP-70 expression in B-cell hematologic malignancy is not limited to CLL/SLL. 1548 57

Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma
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PMID:Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target. 1593 66

Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). Although there have been significant advances in therapy for MM including the use of proteasome inhibitors, t(4;14) MM has a particularly poor prognosis and most patients still die from complications related to their disease or therapy. One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants.
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PMID:FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies. 1609 34

Signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated by Janus kinases (JAKs). Recently, several groups identified a recurrent somatic point mutation constitutively activating the hematopoietic growth factor receptor-associated JAK2 tyrosine kinase in diverse chronic myeloid disorders - most commonly classic myeloproliferative disorders (MPD), especially polycythemia vera. We hypothesized that the JAK2 V617F mutation might also be present in samples from patients with acute myeloid leukemia (AML), especially erythroleukemia (AML-M6) or megakaryoblastic leukemia (AML-M7), where it might mimic erythropoietin or thrombopoietin signaling. First, we documented STAT3 activation by immunoblotting in AML-M6 and other AML subtypes. Immunoperoxidase staining confirmed phosphorylated STAT3 in malignant myeloblasts (21% of cases, including all AML-M3 samples tested). We then analyzed genomic DNA from 162 AML, 30 B-cell lymphoma, and 10 chronic lymphocytic leukemia (CLL) samples for JAK2 mutations, and assayed a subset for SOCS1 and FLT3 mutations. Janus kinase2 V617F was present in 13/162 AML samples (8%): 10/13 transformed MPD, and three apparent de novo AML (one of 12 AML-M6, one of 24 AML-M7, and one AML-M2 - all mixed clonality). FLT3 mutations were present in 5/32 (16%), while SOCS1 mutations were totally absent. Lymphoproliferative disorder samples were both JAK2 and SOCS1 wild type. Thus, while JAK2 V617F is uncommon in de novo AML and probably does not occur in lymphoid malignancy, unexplained STAT3 activation is common in AML. Janus kinase2 extrinsic regulators and other proteins in the JAK-STAT pathway should be interrogated to explain frequent STAT activation in AML.
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PMID:JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. 1659 6


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