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)

B cell lineage non-Hodgkin's lymphomas (NHL-B) are neoplastic B cells that show dysregulated B lymphocyte growth characteristics. Unlike normal B cells, aggressive NHL-B cells show constitutive expression of nuclear NF-kappaB by maintaining an assembled, scaffold-like signaling platform, called a Signalosome within the lipid raft microdomain, extending from the cell membrane. The CD40 Signalosome appears to be initiated through autochthonous production and cognate binding of CD154 (CD40L, gp39) to CD40 by the lymphoma cell. Constitutive expression of NF-kappaB in NHL-B can be downregulated by treatment with antibodies to CD40 or CD154 that disrupt Signalosomes, inhibit lymphoma cell growth, and induce cell death. CD40 Signalosomes may provide a potentially vulnerable target for therapeutic intervention in NHL-B cells.
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PMID:A CD40 Signalosome anchored in lipid rafts leads to constitutive activation of NF-kappaB and autonomous cell growth in B cell lymphomas. 1182 64

The Epstein-Barr virus-encoded latent infection membrane protein 1 (LMP1) is a pleiotropic protein, the activities of which include effects on cell transformation and phenotype, growth, and survival. The ability of LMP1 to mediate at least some of these phenomena could be attributed to the activation of the transcription factor NF-kappaB. LMP1 promotes NF-kappaB activation through the recruitment of the adapter protein TRAF2 and the formation of a dynamic multiprotein complex that includes the NF-kappaB kinase, the IkappaB kinases, and their downstream targets, IkappaBs and p105. In this study, we have identified the oncogenic kinase Tpl-2/Cot as a novel component of LMP1-induced NF-kappaB signaling. We show that Tpl-2 is expressed in primary biopsies from patients with nasopharyngeal carcinoma and Hodgkin's disease, where LMP1 is also found. Inducible expression of LMP1 promotes the activation of Tpl-2, and a catalytically inactive Tpl-2 mutant suppresses LMP1-induced NF-kappaB signaling. In colocalization and coimmunoprecipitation experiments, Tpl-2 and TRAF2 were found to interact with Tpl-2 functioning downstream of TRAF2. Consistent with this observation, catalytically inactive Tpl-2 also blocked CD40-mediated NF-kappaB activation, which largely depends on TRAF2. The ability of Tpl-2 to influence LMP1-induced NF-kappaB occurs through modulation of both IkappaBalpha and p105 functions. Furthermore, Tpl-2 was found to influence the expression of angiogenic mediators, such as COX-2 in LMP1-transfected cells. These data identify Tpl-2 as a component of LMP1 signaling downstream of TRAF2 and as a modulator of LMP1-mediated effects.
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PMID:The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded latent infection membrane protein 1-induced NF-kappaB signaling downstream of TRAF2. 1193 22

Hodgkin's lymphoma (HL) is unusual among human malignancies in that the epidemiology suggests an infectious aetiology. The Epstein-Barr virus (EBV) is associated with a proportion of cases and this association is believed to be causal. In these cases the Hodgkin and Reed-Sternberg (HRS) cells express the EBV-encoded proteins LMP1 and LMP2, which can mimic CD40 and the B cell receptor, respectively, and therefore may play a critical role in facilitating the survival of HRS cells. EBV-associated and non-EBV-associated HL cases have different epidemiological features and recent data suggest that delayed exposure to EBV is a risk factor for the development of EBV-associated HL in young adults. We suggest that HL can be divided into four entities on the basis of EBV status and age at presentation, with three groups of EBV-associated cases and a single group of EBV-negative cases. The aetiology of the latter cases is obscure although involvement of an infectious agent(s) is suspected.
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PMID:Viruses and Hodgkin's lymphoma. 1207 98

The mitogen-activated protein kinase (MAPK) (also called extracellular signal-regulated kinase [ERK]) pathway has been implicated in malignant transformation and in the regulation of cellular growth and proliferation of several tumor types, but its expression and function in Hodgkin disease (HD) are unknown. We report here that the active phosphorylated form of MAPK/ERK is aberrantly expressed in cultured and primary HD cells. Inhibition of the upstream MAPK kinase (also called MEK) by the small molecule UO126 inhibited the phosphorylation of ERK and demonstrated a dose- and time-dependent antiproliferative activity in HD cell lines. UO126 modulated the levels of several intracellular proteins including B-cell lymphoma protein 2 (Bcl-2), myeloid cell leukemia-1 (Mcl-1) and caspase 8 homolog FLICE-inhibitory protein (cFLIP), and induced G2M cell-cycle arrest or apoptosis. Furthermore, UO126 potentiated the activity of apoliprotein 2/tumor necrosis factor-related apoptosis-inducing ligand (APO2L/TRAIL) and chemotherapy-induced cell death. Activation of CD30, CD40, and receptor activator of nuclear kappabeta (RANK) receptors in HD cells by their respective ligands increased ERK phosphorylation above the basal level and promoted HD cell survival. UO126 inhibited basal and ligand-induced ERK phosphorylation, and inhibited ligand-induced cell survival of HD cell lines. These findings provide a proof-of-principle that inhibition of the MEK/ERK pathway may have therapeutic value in HD.
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PMID:MEK/ERK pathway is aberrantly active in Hodgkin disease: a signaling pathway shared by CD30, CD40, and RANK that regulates cell proliferation and survival. 1268 28

Chromosomal rearrangements in non-Hodgkin's B-cell lymphoma implicate BCL-6 as an oncogene, yet direct evidence for BCL-6 acting as an oncogene in B cells has been lacking. Here, we show that BCL-6 can immortalize primary B cells, but only in the absence of p53 tumor suppressor function. The expression of BCL-6 led to greatly increased B-cell proliferation, particularly in response to CD40 stimulation. Furthermore, BCL-6-infected p53-deficient B cells gave rise to immortalized cell lines that could be maintained by CD40 stimulation. We found that in primary mouse B cells, BCL-6 repressed expression of the Blimp-1, p27kip1, and cyclin D2 target genes. BCL-6 did not markedly repress the PDCD2 and BCL-XL target genes. The BCL-6 immortalized cell lines had a phenotype consistent with germinal center B cells, they expressed the germinal center-specific M17 gene, and a significant fraction of the cells stained positive with PNA. Our data indicate that BCL-6 may act to maintain B cells in a germinal center-like state, and repression of Blimp-1 by BCL-6 may be particularly crucial for stabilization of the germinal center phenotype. Our data also suggest that disruption of the p53 pathway may be crucial for the development of BCL-6-expressing B-cell lymphomas.
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PMID:Transcriptional repressor BCL-6 immortalizes germinal center-like B cells in the absence of p53 function. 1473 19

The incidence of lymphomas is high among HIV infected patients. These lymphomas are non-Hodgkin's lymphoma (NHL) in 70% of cases and Hodgkin's disease (HD) in 30% of cases. Their localization is often extra-nodal with early dissemination. B-cell high grade NHL predominates. The most frequent histological types are diffuse large B-cell lymphoma (30 to 40%) and Burkitt's lymphoma (40 to 50%). Other histological types are low-grade B-cell lymphoma, polymorphic B cell lymphoma and primary effusion lymphoma. Three main factors are predominant in HIV-related lymphomagenesis: cellular immunodeficiency, oncogene viruses (Epstein-Barr and HHV8) and molecular lesions. HIV-related cellular immunodeficiency leads to the increase of EBV infected B-cells and to the diminution of antitumor immunity. Clonal EBV genome is found in lymphoma cells in 30 to 70% of cases of HIV-related NHL. It expresses oncogenic proteins including LMP-1 which behaves like an activated CD40. It induces the expression of intra-cellular genes which stimulate cell growth and inhibit apoptosis. Cytogenetic and molecular lesions are not specific to HIV-related NHL or to histological subtypes. A better knowledge of these mechanisms should lead to the development of specific targeted treatments (antiviral, cytotoxic anti-EBV lymphocytes, cell cycle regulators).
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PMID:[Lymphoma genesis in the context of HIV infection]. 1503 28

Mantle cell lymphoma (MCL) is an aggressive subentity of non-Hodgkin lymphoma (NHL), responds poorly to therapy, is resistant to current therapeutic strategies and has the shortest survival of all lymphoma entities. The blastoid variant of mantle cell lymphoma (MCL-BV) has an even worse clinical outcome. The mechanisms of neoplastic transformation from normal mantle cells and the relationship to the rare blastoid variant are poorly understood. BCL2 is overexpressed in indolent B-cell NHL including MCL. In addition, other proteins of the BCL-family are overexpressed in MCL like BCLX, whereas the expression of BAX and BAK was not elevated in MCL. BCL2 independent apoptotic pathways are altered in MCL. CD40, which can mediate B-cell survival, is overexpressed in MCL. Furthermore, the expression of FAS which is known to be pro-apoptotic is markedly decreased favoring the CD40 mediated cell survival pathway in these cells. Besides overexpression of cyclin D1, the cyclin dependent kinases (CDK2 and CDK4) are highly expressed in MCL resulting in the phosphorylation of RB1, E2F release, and the cell cycle progression. The new technique of gene expression analysis by microarrays promotes more insight into the pathogenesis of MCL and discovery of altered cell signaling pathways, and the ability to predict subgroups of patients with different risk and probability of response to treatment.
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PMID:Altered apoptosis pathways in mantle cell lymphoma. 1506 Nov 96

Mantle cell lymphoma (MCL) is a CD5+ non-Hodgkin's B-cell lymphoma characterized by the infiltration of intermediate sized B-cells into the mantle zones. Interaction between CD40L and CD40 is important for B cell proliferation and differentiation. CD40L stimulation can induce both growth arrest and proliferation of B cell lines according to their differentiation state. Previous reports examining the effect of stimulation via the CD40 cascade on ex vivo MCL cells have provided conflicting results. In this study, two MCL lines, SP49 and SP53, were examined for response to CD40L and/or IL-10. Co-cultivation with CD40L-expressing mouse L cells reduced the BrdU incorporation of SP49 and SP53 cells by half to one-third, while BrdU incorporation of control cell lines, including Ramos, BJAB and BALL-1, was not affected or increased. Anti-CD40L antibody blocked the CD40L inhibition of SP49 cell proliferation in a dose-dependent manner in the range from 0 to 20 ng/ml. IL-10 did not affect MCL cell proliferation in the presence or absence of CD40L-expressing cells, while Ramos proliferation was promoted by CD40L and IL-10. These results suggested the possibility that CD40L may also inhibit MCL proliferation in vivo.
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PMID:CD40 ligand stimulation inhibits the proliferation of mantle cell lymphoma lines. 1516 Oct 13

The most frequently recurring translocations in mucosa-associated lymphoid tissue (MALT) B-cell non-Hodgkin lymphoma, t(11;18)(q21;q21) and t(14;18)(q32; q21), lead to formation of an API2-MALT1 fusion or IgH-mediated MALT1 overexpression. Various approaches have implicated these proteins in nuclear factor kappaB (NF-kappa B) signaling, but this has not been shown experimentally in human B cells. Immunohistochemistry showed that MALT1 is predominantly expressed in normal and malignant germinal center B cells, corresponding to the differentiation stage of MALT lymphoma. We expressed MALT1 and apoptosis inhibitor-2 API2/MALT1 in human B-cell lymphoma BJAB cells and found both transgenes in membrane lipid rafts along with endogenous MALT1 and 2 binding partners involved in NF-kappa B signaling, B-cell lymphoma 10 (BCL10) and CARMA1 (caspase recruitment domain [CARD]-containing membrane-associated guanylate kinase [MAGUK] 1). API2-MALT1 and exogenous MALT1 increased constitutive NF-kappa B activity and enhanced I kappa B kinase (IKK) activation induced by CD40 stimulation. Both transgenes protected BJAB cells from FAS (CD95)-induced death, consistent with increases in NF-kappa B cytoprotective target gene expression, and increased their proliferation rate. Expression of a dominant-negative I kappa B alpha mutant showed that these survival and proliferative advantages are dependent on elevated constitutive NF-kappa B activity. Our findings support a model in which NF-kappa B signaling, once activated in a CD40-dependent immune response, is maintained and enhanced through deregulation of MALT1 or formation of an API2-MALT1 fusion.
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PMID:MALT1 and the API2-MALT1 fusion act between CD40 and IKK and confer NF-kappa B-dependent proliferative advantage and resistance against FAS-induced cell death in B cells. 1559 10

Epstein-Barr virus (EBV) is associated with B-cell lymphomas such as Hodgkin lymphoma, Burkitt lymphoma, and post-transplantation lymphoma, which originate from clonal germinal center (GC) B cells. During the process of somatic hypermutation, GC B cells can acquire deleterious or nonsense mutations in the heavy and light immunoglobulin genes. Such mutations abrogate the cell surface expression of the B-cell receptor (BCR), which results in the elimination of these nonfunctional B cells by immediate apoptosis. EBV encodes several latent genes, among them latent membrane protein 1 (LMP1) and LMP2A, which are regularly expressed in EBV-positive Hodgkin lymphoma and posttransplantation lymphomas. Since LMP1 and LMP2A mimic the function of 2 key receptors on B cells, CD40 and BCR, respectively, we wanted to learn whether EBV infection can rescue proapoptotic GC B cells with crippling mutations in the heavy chain immunoglobulin locus from apoptosis. We show here that BCR-negative GC B cells readily enter the cell cycle upon infection with EBV in vitro and yield clonal lymphoblastoid cell lines that are incapable of expressing a functional BCR because the rearranged and formerly functional heavy chain immunoglobulin alleles carry deleterious mutations. Our findings imply an important role for EBV in the process of lymphomagenesis in certain cases of Hodgkin lymphoma and posttransplantation lymphomas.
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PMID:Rescue of "crippled" germinal center B cells from apoptosis by Epstein-Barr virus. 1607 66


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