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

Although bispecific antibodies directed against malignant lymphoma have been shown to be effective in vitro and in vivo, extended clinical trials so far have been hampered by the fact that conventional approaches to produce these antibodies suffer from low yields, ill-defined byproducts, or laborious purification procedures. To overcome this problem, we have generated a small, recombinant, lymphoma-directed, bispecific single-chain (bsc) antibody according to a novel technique recently described. The antibody consists of 2 different single-chain Fv fragments joined by a glycine-serine linker. One specificity is directed against the CD3 antigen of human T cells, and the other antigen-binding site engages the pan-B-cell marker CD19, uniformly expressed on the vast majority of B-cell malignancies. The construct was expressed in Chinese hamster ovary cells and purified by its C-terminal histioline tag. Specific binding to CD19 and CD3 was demonstrated by fluorescence-activated cell sorter analysis. By redirecting unstimulated primary human T cells derived from the peripheral blood against CD19-positive lymphoma cells, the bscCD19 x CD3 antibody showed significant cytotoxic activity at very low concentrations of 10 to 100 pg/mL and at effector to target cell ratios as low as 2:1. Moreover, strong lymphoma-directed cytotoxicity at low antibody concentrations was rapidly induced during 4 hours even in experiments without any T-cell prestimulation. Thus, this particular antibody proves to be much more efficacious than the bispecific antibodies described until now. Therefore, the described bscCD19 x CD3 molecule should be a suitable candidate to prove the therapeutic benefit of bispecific antibodies in the treatment of non-Hodgkin lymphoma. (Blood. 2000;95:2098-2103)
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PMID:A recombinant bispecific single-chain antibody, CD19 x CD3, induces rapid and high lymphoma-directed cytotoxicity by unstimulated T lymphocytes. 1070 80

For the treatment of Hodgkin lymphoma, bispecific monoclonal antibodies (bi-mAbs) were established which recognize the Hodgkin-associated CD30 antigen with one arm and the CD3 or CD28 antigen on T lymphocytes or the CD16 antigen on natural killer (NK) cells with the second arm. The NK cell-activating alpha-CD16/CD30 antibody was able to retarget human NK cells toward CD30- target cells and induce their lysis. Sixty percent of Hodgkin tumor-bearing severe combined immunodeficient mice responded to a combined treatment with bi-mAb and human NK cells, leading to a final cure rate of 20%. T cell-activating bi-mAbs were more effective, resulting in the cure of all mice treated. The in vivo administration of both alpha-CD3/CD30 and alpha-CD28/CD30 antibodies resulted in the specific activation of resting human T cells infiltrating the CD30+ Hodgkin tumors. Tumor-infiltrating lymphocytes in the group of mice treated with both T cell-activating bi-mAbs expressed high levels of cytokines and cytotoxic molecules such as perforin and the cytotoxic serine esterases granzyme A and B. More importantly, activated T cells did not home to CD30 tissue and did not enter the circulation. Encouraged by these preclinical data, 15 patients with treatment-refractory Hodgkin lymphoma were included in a phase I/II dose-escalation study and treated four times every 3 or 4 days with increasing doses of the alpha-CD16/CD30 bi-mAb ranging from 1 mg/m2 to 128 mg/m2. No dose-limiting toxicity occurred even at the highest doses. Of these 15 patients, one had a complete response, one a partial response, three a mixed response, two stable disease, and eight patients had progressive disease. Treatment with immunological effector cell-recruiting bi-mAbs is a promising new approach to the treatment of Hodgkin disease refractory to standard therapy.
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PMID:Immune recruitment by bispecific antibodies for the treatment of Hodgkin disease. 1095 Jan 45

The CHK2 gene encodes a protein kinase that is important for the regulation of cell cycle arrest after DNA damage. CHK2 acts downstream of ataxia teleangiecstasia mutated (ATM), modulates the function of p53 and may help mediate cell cycle arrest at G2/M by phosphorylation of Cdc25C. Recently, the human homolog of the checkpoint kinase Cds1 (CHK2) has been suggested to be a tumor suppressor gene. Heterozygous germline mutations have been reported in Li-Fraumeni syndrome (LFS), a highly penetrant familial cancer phenotype, and in sporadic colon cancer. LFS is associated with the development of lymphoid malignancies, especially childhood ALL. Therefore, we analyzed the DNA from 143 lymphoid malignancies to determine whether they had mutations of the CHK2 gene. The 14 exons of CHK2 were studied by polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and sequencing of aberrantly migrating bands. One missense mutation changing serine to phenylalanine (codon 428) in an evolutionarily highly conserved domain was found in a non-Hodgkin's aggressive lymphoma. Another point mutation in the non-coding region was identified in one of adult T-cell leukemias (ATL) samples. This result suggests that mutation of the CHK2 gene may rarely be involved in the development of selected lymphomas.
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PMID:Analysis of the CHK2 gene in lymphoid malignancies. 1169 18

Anaplastic large-cell lymphoma is a subtype of non-Hodgkin lymphomas characterized by the expression of CD30. More than half of these lymphomas carry a chromosomal translocation t(2;5) leading to expression of the oncogenic tyrosine kinase nucleophosmin-anaplastic lymphoma kinase (NPM-ALK). NPM-ALK is capable of transforming fibroblasts and lymphocytes in vitro and of causing lymphomas in mice. Previously, we and others demonstrated phospholipase C-gamma and phosphatidylinositol 3-kinase as crucial downstream signaling mediators of NPM-ALK-induced oncogenicity. In this study, we used an ALK fusion protein as bait in a yeast two-hybrid screen identifying NIPA (nuclear interacting partner of ALK) as a novel downstream target of NPM-ALK. NIPA encodes a 60-kDa protein that is expressed in a broad range of human tissues and contains a classical nuclear translocation signal in its C terminus, which directs its nuclear localization. NIPA interacts with NPM-ALK and other ALK fusions in a tyrosine kinase-dependent manner and is phosphorylated in NPM-ALK-expressing cells on tyrosine and serine residues with serine 354 as a major phosphorylation site. Overexpression of NIPA in Ba/F3 cells was able to protect from apoptosis induced by IL-3 withdrawal. Mutations of the nuclear translocation signal or the Ser-354 phosphorylation site impaired the antiapoptotic function of NIPA. In NPM-ALK-transformed Ba/F3 cells, apoptosis triggered by wortmannin treatment was enhanced by overexpression of putative dominant-negative NIPA mutants. These results implicate an antiapoptotic role for NIPA in NPM-ALK-mediated signaling events.
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PMID:Identification and characterization of a nuclear interacting partner of anaplastic lymphoma kinase (NIPA). 1274 72

Chromosomal translocations and somatic mutations occurring in the 5' noncoding region of the BCL6 gene, encoding a transcriptional repressor, are most frequent genetic abnormalities associated with non-Hodgkin B-cell lymphoma and result in deregulated expression of BCL6. However, the significance of deregulated expression of BCL6 in lymphomagenesis and its effect on clinical outcomes of lymphoma patients have remained elusive. In the present study, we established Daudi and Raji B-cell lymphoma cell lines that overexpress BCL6 or its mutant, BCL6-Ala333/343, in which serine residues required for degradation through the proteasome pathway in B-cell receptor-stimulated cells are mutated. BCL6 overexpression did not have any significant effect on cell proliferation, but significantly inhibited apoptosis caused by etoposide, which induced a proteasome-dependent degradation of BCL6. BCL6-Ala333/343 was not degraded after etoposide treatment and strongly inhibited apoptosis. In these lymphoma cell lines, etoposide increased the generation of reactive oxygen species (ROS) and reduced mitochondria membrane potential, both of which were inhibited by the antioxidant N-acetyl-L-cysteine (NAC). NAC also inhibited apoptosis. Furthermore, BCL6 overexpression was found to inhibit the increase in ROS levels and apoptosis in response to etoposide and other chemotherapeutic reagents. These results raise the possibility that deregulated expression of BCL6 may endow lymphoma cells with resistance to chemotherapeutic reagents, most likely by enhancing the antioxidant defense systems.
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PMID:BCL6 overexpression prevents increase in reactive oxygen species and inhibits apoptosis induced by chemotherapeutic reagents in B-cell lymphoma cells. 1288 2

Ki-1/57, the 57-kDa human protein antigen recognized by the CD30 antibody Ki-1, is a cytoplasmic and nuclear protein that is phosphorylated on serine and threonine residues. When isolated from the Hodgkin's lymphoma analogous cell line L540 Ki-1/57 co-immunoprecipitated with a Thr/Ser protein kinase activity. It has been also found to interact with hyaluronic acid and has therefore been termed intracellular IHABP4 (hyaluronan-binding protein 4). Recent studies demonstrated, however, that Ki-1/57 engages in specific interaction with the chromo-helicase-DNA-binding domain protein 3, a nuclear protein involved in chromatin remodeling and transcription regulation. We used the yeast two-hybrid system to find proteins interacting with Ki-1/57 and identified the adaptor protein RACK1 (receptor of activated kinase 1). Next, we confirmed this interaction in vitro and in vivo, performed detailed mapping studies of the interaction sites of Ki-1/57 and RACK-1, and demonstrated that Ki-1/57 also co-precipitates with protein kinase C (PKC) when isolated from phorbol 12-myristate 13-acetate (PMA)-activated L540 tumor cells and is a substrate for PKC phosphorylation in vitro and in vivo. Interestingly, the interaction of Ki-1/57 with RACK1 is abolished upon activation of L540 cells with PMA, which results in the phosphorylation of Ki-1/57 and its exit from the nucleus. Taken together, our data suggest that Ki-1/57 forms a stable complex with RACK-1 in unstimulated cells and upon PMA stimulation gets phosphorylated on threonine residues located at its extreme C terminus. These events associate Ki-1/57 with the RACK1/PKC pathway and may be important for the regulation of its cellular functions.
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PMID:Ki-1/57 interacts with RACK1 and is a substrate for the phosphorylation by phorbol 12-myristate 13-acetate-activated protein kinase C. 1469 38

Polo-like kinases (PLKs) are protein serine/threonine kinases that play important roles in cell division. Expression of PLK1 might, moreover, play a role in the pathogenesis of human neoplasms. The expression of PLK1 mRNA is closely correlated with survival in patients with malignant tumors. We investigated the expression of PLK1 in non-Hodgkin's lymphomas (NHLs) and analyzed the relationships between expression of PLK1, histological grade, and prognosis. We analyzed various types of NHLs from 118 patients using monoclonal antibodies against PLK1 and Ki-67. The levels of expression of PLK1 and Ki-67 were significantly lower in low-grade NHLs than in high-grade and intermediate-grade NHLs (P < 0.001). Moreover, when patients were grouped in terms of 5-year overall survival ( > 70%, group A; 50 - 70%, group B; 30 - 49%, group C; and < 30%, group D), levels of expression of PLK1 and Ki-67 were found to be significantly higher in group D than in group A and they were also significantly higher in group C than in group A (P < 0.001). Conversely, the level of expression, of Ki-67 was significantly lower in group D than in group C (P < 0.05). The labeling indices specific for PLK1 were generally higher than those specific for Ki-67. Once we divided all patients into two groups in terms of the expression levels, high-level expression group of PLK1 (PLK1 index of 70%) and Ki-67 (Ki-67 indices of 60%) and low-level expression, one of these markers (PLK1 index of >/= 70%, Ki-67 indices of >/= 60%) had a similar prognosis, an observation that can be explained by the fact that rapidly proliferating group is more drug-sensitive than the other. Our study demonstrates that expression of PLK1 might reflect the malignant potential of NHLs and that PLK1 might be more useful than Ki-67 for the detection of proliferative cells.
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PMID:Expression of Polo-Like Kinase (PLK1) in non-Hodgkin's lymphomas. 1562 5

Cellular Jun (c-Jun), a member of the JUN family, is an activator protein-1 transcription factor involved in cell differentiation, proliferation, and apoptosis that can be activated by phosphorylation at serine-73 and -63 residues. Using tissue microarrays and immunohistochemistry, we investigated c-Jun expression and serine-73 phosphorylation in 112 CD30 lymphomas and 232 CD30 lymphomas of B- or T-cell lineage, and 24 cases of lymphomatoid papulosis. c-Jun was expressed exclusively by CD30 lymphoproliferative disorders including 41/41 (100%) classical Hodgkin lymphoma (cHL), 20/23 (87%) anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL), 18/26 (69%) ALK- ALCL, 5/9 (56%) primary cutaneous ALCL, 4/11 (36%) CD30 diffuse large B-cell lymphoma (DLBCL), and 11/24 (46%) cases of lymphomatoid papulosis. The percentage of c-Jun-positive tumor cells was highest in cHL and ALCL (P=0.002). In contrast, all CD30 lymphomas, including nodular lymphocyte predominant HL and CD30 non-Hodgkin lymphomas of B- or T-cell lineage were negative for c-Jun. Serine-73 phosphorylated c-Jun (p-c-Jun), the activated form of c-Jun, was expressed more frequently and at a higher level in cHL and ALK+ ALCL than other CD30 tumors. The percentage of p-c-Jun-positive tumor cells correlated significantly with the percentage of total c-Jun-positive cells (P<0.0001), suggesting that activated c-Jun positively regulates total c-Jun levels in CD30 lymphomas through a well-established positive feedback loop. We conclude that CD30 lymphomas are characterized by common patterns of c-Jun expression and activation suggesting a potential role of c-Jun in the pathogenesis of these tumors.
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PMID:c-Jun expression and activation are restricted to CD30+ lymphoproliferative disorders. 1732 87

The Hodgkin-Reed-Sternberg (HRS) malignant cells in Hodgkin's lymphoma (HL) originate from germinal center B lymphocytes that did not undergo apoptosis. Protein Kinase C (PKC), a family of serine/threonine kinases, plays a crucial role in signal transduction modulating cell growth, differentiation and apoptosis. Here, we report the expression of PKC isoforms in two HL-derived cell lines, L428 and KMH2 and their correlation with drug resistance to CPT and doxorubicin. Among the PKC isoforms examined, only PKCeta and PKCbetaII were preferentially expressed in the drug resistant L428 cells. We have shown correlation between the response to apoptosis of L428 and KMH2 cells and PKCeta expression in these cell lines. In order to directly demonstrate a role for PKCeta in apoptosis, its expression was knocked-down by siRNA in the resistant L428 cells. Downregulation of PKCeta rendered L428 cells more sensitive to doxorubicin and CPT. Furthermore, PKCeta knocked-down cells showed increased PARP-1 cleavage, cytochrome c release and caspase 7 activation. It appears that PKCeta functions as an anti-apoptotic protein in HL-derived cell lines, and as we show here that it is also expressed in HRS of HL biopsies, it may have therapeutic relevance in HL. Thus, PKCeta could provide a new target aimed to reduce resistance to anti-cancer treatments of HL and other cancer patients.
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PMID:PKCeta expression contributes to the resistance of Hodgkin's lymphoma cell lines to apoptosis. 1778 31

Mantle cell lymphoma (MCL) is a clinically aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13;q32) and overexpression of cyclin D1. A high proportion of MCL tumors harbor wild-type (wt) and potentially functional p53 gene. We show here that stabilization and activation of wt-p53 using a recently developed potent MDM2 inhibitor, nutlin 3A, results in significant p53-dependent G1-S cell cycle arrest and apoptosis in MCL cells through regulation of p53 target genes. As mTOR signaling is activated in MCL and may control cyclin D1 levels, we show that p53 activation may downregulate the AKT/mTOR pathway through a mechanism involving AMP kinase (AMPK). Despite the non-genotoxic mode of nutlin 3A treatment, we show evidence that stabilization of p53 is associated with its phosphorylation at serine 15 residue and activation of AMPK. Stimulation of AMPK kinase activity using AICAR inhibits phosphorylation of critical downstream effectors of mTOR signaling, such as 4E-BP1 and rpS6. Pharmacologic inhibition of AMPK using compound C in nutlin-3A-treated MCL cells harboring wt-p53 did not affect the level of (ser15)p-p53, suggesting that the (ser15)p-p53 --> AMPK is the direction involved in the p53/AMPK/mTOR cross talk. These data establish a p53 --> AMPK --> mTOR mechanism in MCL and uncover a novel biologic effect of potent MDM2 inhibitors in preclinical models of MCL.
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PMID:Stabilization and activation of p53 downregulates mTOR signaling through AMPK in mantle cell lymphoma. 1922 36


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