Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The in vitro analysis of growth regulation in low-grade B non-Hodgkin's lymphoma (B-NHL) is hampered by the rapid apoptotic death of the malignant B cells ex vivo. A complex culture system, using murine CDw32 transfected fibroblasts (LTK-cells), IL-4 and anti-CD40 mAb, has been established for the propagation of normal mature B cells in vitro. We investigated the influence of the different components of this coculture system on cell survival and apoptosis of B-NHL cells. Nine samples from patients with follicular lymphoma and from eight patients with immunocytoma were analyzed. No cell proliferation of B-NHL cells could be induced in the culture system. However, CDw32-transfected murine fibroblasts most efficiently supported cell viability of B-NHL cells with an increase in cell survival by 114% compared to the control (P = 0.047). IL-4 alone also had a stimulatory effect on cell survival of B-NHL cells after 6 days. In contrast, the soluble recombinant CD40 ligand gp39 and the anti-CD40 mAbs mAb89 and EA-5 did not prolong cell survival. CDw32 transfectants blocked apoptosis of B-NHL cells efficiently from 67% in the control to 16% (P = 0.001). Reduction in apoptosis was accompanied by an elevated bcl-2 protein expression. IL-4 or mAb89 did not further reduce apoptotic cell death in CDw32 transfectant-dependent cocultures. Our data underline the pivotal role of LTK- cells for cell survival of B-NHL cells in vitro. The efficient blockage of apoptosis associated with increased bcl-2 protein expression causes prolonged cell viability of the B-NHL cells.
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PMID:In vitro activation of low-grade non-Hodgkin's lymphoma by murine fibroblasts, IL-4, anti-CD40 antibodies and the soluble CD40 ligand. 936 19

Acquired chromosomal anomalies (most commonly translocations) in lymphoma and leukemia usually result in either activation of a quiescent gene (by means of immunoglobulin or T-cell-receptor promotors) and expression of an intact protein product, or creation of a fusion gene encoding a chimeric protein. This review summarizes current immunocytochemical studies of these 2 categories of oncogenic protein, with emphasis on the clinical relevance of their detection in diagnostic samples. Among the quiescent genes activated by rearrangement, expression of cyclin D1 (due to rearrangement of the CCND1 [BCL-1] gene) is a near-specific marker of t(11;14) in mantle cell lymphoma; BCL-2 expression distinguishes follicular lymphoma cells from their nonneoplastic counterparts in reactive germinal centers and appears to be an independent prognostic marker in diffuse large cell lymphoma; and TAL-1 (SCL) expression identifies T-cell acute lymphoblastic neoplasms in which this gene is activated. The protein products of other genes activated by chromosomal rearrangement have a role as markers of either lineage (eg, PAX-5 [B-cell-specific activator protein] for B cells, including B-lymphoblastic neoplasms), or maturation stage (eg, BCL-6 for germinal-center and activated B cells and MUM-1/IRF4 for plasma cells). Currently, no hybrid protein encoded by fusion genes is reliably detectable by antibodies recognizing unique junctional epitopes (ie, epitopes absent from the wild-type constituent proteins). Nevertheless, staining for promyelocytic leukemia (PML) protein will detect acute PML with t(15;17) because the microspeckled nuclear labeling pattern for PML-RARalpha is highly distinctive. Similarly, antibodies to the anaplastic lymphoma kinase (ALK) tyrosine kinase are valuable (because wild-type ALK is not found in normal lymphoid tissue) in detecting neoplasms (CD30-positive large T-cell lymphomas) with t(2;5) or its variants. Thus, immunocytochemical detection of the products of many rearranged genes in lymphoma and leukemia can be clinically informative and provide information on cellular and subcellular protein expression that cannot be inferred from studies based on messenger RNA.
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PMID:Proteins encoded by genes involved in chromosomal alterations in lymphoma and leukemia: clinical value of their detection by immunocytochemistry. 1178 Dec 20

We have previously reported that plasma from patients with anaplastic lymphoma kinase (ALK)-positive lymphoma contains antibodies against the oncogenic kinase NPM-ALK protein characteristic of this disease. We investigated whether this reactivity represents a phenomenon unique to ALK-positive lymphoma by screening plasma from patients with follicular lymphoma for antibodies to BCL-2 protein. Eight out of 10 samples showed such reactivity (and in six cases gave specific staining of BCL-2-transfected cells). As these findings suggest a new biochemical approach to the identification of oncogenic proteins in lymphoma, we investigated whether antibodies present in patients with ALK-positive lymphoma can precipitate NPM-ALK in quantities which should be sufficient for further analysis. We found that plasma samples from all10 patients studied immunoprecipitated NPM-ALK asaprotein visible in silver-stained sodium dodecyl sulphatepolyacrylamide gels. Finally we demonstrated that NPM-ALK could be visualized more clearly if it were immunoprecipitated from extracts of cells in which newly synthesized proteins had been labelled with 35S and then identified by autoradiography. These results suggest a strategy for using patients' autoantibodies to screen for antibodies to other tumour-associated proteins.
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PMID:Immunochemical studies of antigenic lymphoma-associated proteins. 1184 6

In peripheral blood of at least 50% of healthy individuals, the translocations t(9;22) BCR/ABL, t(14;18) IgH/BCL-2, t(2;5) NPM-ALK and MLL duplications, which characterize chronic myelogenous leukemia and acute lymphoblastic leukemia, follicular lymphoma, anaplastic large cell lymphoma, and acute myelogenous leukemia, respectively, are detectable by sensitive polymerase chain reaction (PCR). No structural differences between these aberrations in normal or disturbed hematopoiesis are apparent. While the total count of t(9;22)- and t(14;18)-positive cells does not exceed 10(4), those with MLL duplications are more frequent and account for approximately 10(7) cells in the total blood pool. t(14;18)-positive cells seem to be immortalized, but the biological consequences of the other aberrations in positive healthy persons have not been studied in detail. Due to the high frequency of positive individuals, most of them will not suffer from the correspondent leukemia or lymphoma, and criteria for subgroups that may be at a higher risk remain to be determined. Most likely, the number of genetic aberrations in healthy individuals, which so far are only associated with hematopoietic disorders, will increase in the near future.
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PMID:Leukemia- and lymphoma-associated genetic aberrations in healthy individuals. 1190 85

Cytogenetic analysis including multicolor spectral karyotyping (SKY) and interphase fluorescence in situ hybridization (FISH) was performed on 154 consecutive cases with suspected lymphoma. The cytogenetic results were reviewed in correlation with the final pathologic diagnosis. A diagnosis of lymphoma was established in 94 cases, with 16 Hodgkin lymphomas and 78 non-Hodgkin lymphomas (NHL). Cytogenetic results were obtained in 63 NHLs (81%); 61 of those showed abnormal karyotypes (97%). The t(14;18) or IGH-BCL2 fusion was detected in 83% (20/24) of follicular lymphomas and in 57% (12/21) of diffuse large B-cell lymphomas (DLBCL). The application of interphase FISH and SKY has contributed to a high detection rate of t(14;18) in DLBCLs. This study showed that genes at 1q25, 3p21, 3q21, 5q31, 6p23, 7q22, 8q11 approximately q12, 9q34, 11q23, 12q13, and 19q13.1 may have been involved as the less common changes in follicular lymphoma and DLBCL. Comparison of the recurrent secondary aberrations in the groups of follicular lymphoma and DLBCL revealed a pattern of clonal evolution from the changes rea(1)(p36), del(6q), +7, +12 or dup or trp(12)(q13q22), +der(18)t(14;18), and +21 in follicular lymphoma to the changes rea(1)(p36), del(6q), +6, +7, +9, rea(11)(q23), +12, -13 or del(13(q12q14), +18, +21, and +X in DLBCL. The clonal evolution of the secondary aberrations is thought to contribute to the progression of the disease. About 90% (16/18) of other types of NHL had abnormal karyotypes showing specific translocations or gene rearrangements consistent with the pathologic diagnosis. A comprehensive cytogenetics approach including SKY and interphase FISH using probes for specific genes, such as IGH, BCL2, CCND1, and ALK, is a very useful ancillary diagnostic tool for lymphomas. The combined approach also led to the identification of t(2;19)(p23;q13.1) as a new variant of t(2;5)(p23;q35) in a case of Ki-1-positive anaplastic large cell lymphoma with a null cell phenotype.
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PMID:Comprehensive cytogenetic analysis including multicolor spectral karyotyping and interphase fluorescence in situ hybridization in lymphoma diagnosis. a summary of 154 cases. 1274 58

Mouse, chimeric, humanized and human monoclonal antibodies (MABs) are all in use for treatment of human cancer. Unconjugated antibodies have a complex mechanism of action, dependent on the nature of the target structure. Antibodies can activate the immune system (antibody-dependent cellular cytotoxicity [ADCC], complement-dependent cytotoxicity [CDC], induction of tumor immunity [idiotype network]). ADCC appears to be one of the most important immune effector functions. Antibodies may also induce apoptosis, cell cycle arrest, inhibition of cell proliferation as well as angiogenesis and metastatic spread. For most antibodies there is no clear dose-response relationship in vivo. The effect of antibodies can be enhanced by combination with chemotherapy and/or by agents which activate the immune system. The best therapeutic effect may be obtained if MABs are used early in the course of the disease. Rituximab (anti-CD20) was the first registered MAB for the therapy of follicular lymphoma. Impressive results have been seen in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) in follicular and high-grade lymphomas. In other non-Hodgkin's lymphoma subtypes, promising results are also seen in combination with chemotherapy. Trastuzumab (anti-Her2) is a breakthrough in the treatment of breast cancer in combination with chemotherapeutic agents. This antibody is also in clinical testing for adjuvant treatment. Alemtuzumab (anti-CD52) has shown impressive results both in refractory chronic lymphocytic leukemia and as up-front therapy. There are many other antibodies in late stages of testing for registration. Interesting MABs include cetuximab (anti-epidermal growth factor receptor [EGFR]), especially in combination with radiotherapy in head and neck cancer; ABX-EGF (anti-EGFR) in renal carcinoma; bevacizumab (anti-vascular endothelial growth factor) in several solid tumors. Antiepithelial cell adhesion molecule antibodies show promise in combination with chemotherapy in the adjuvant setting of colorectal carcinoma. It is estimated that about 20 antibodies will be in clinical use by the year 2010.
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PMID:Monoclonal antibodies in human cancer. 1498 43

The WHO classification of malignant lymphoma presents a list of disease entities well defined by clinical, immunologic and genetic features. The disease entities are primarily exemplified by mantle cell lymphoma (the relative incidence, 3%, related with an aberrant expression of cyclin D1 activated by t(11;14) chromosomal translocation), follicular lymphoma (7%, with BCL2 by t(14;18) translocation), marginal zone B-cell lymphoma of MALT type (8%, with MALT1 by t(11;18) or t(14;18) translocation), adult T-cell leukemia/lymphoma (7%, but 20% in Kyushu, with human T-cell leukemia virus type 1 [HTLV1]), extranodal NK/T-cell lymphoma of nasal type (2%, with Epstein-Barr virus [EBV]), and anaplastic large cell lymphoma (2%, with ALK by t(2;5) translocation). The genetic alterations or agents related with their pathogenesis are of great relevance to the diagnoses of these entities. Conversely, the category of diffuse large B-cell lymphoma occupies the largest percentage (33%), and is heterogeneous, including several subtypes. The diagnoses of lymphoma subtypes, except for the main entities described above, largely depends on the phenotypic analysis, in addition to their clinical manifestations and histologic evaluations. Therefore, much attention should be paid to the diagnostic pitfalls in the phenotypic analysis of T-cell lymphomas in regard to incorrect classification of lymphoma, due to lack of awareness or incomplete immunophenotypic evaluation; incorrect interpretation of immunophenotypic data, due to failure to correlate them with the other laboratory data; and suboptimal quality of immunohistochemical stains, leading to a wrong conclusion.
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PMID:[World Health Organization (WHO) classification of malignant lymphoma--how is the WHO now?]. 1499 43

Heat-shock protein-90 (HSP90) inhibitors are currently being used in phase I clinical trials for treating patients with a variety of neoplasms including lymphomas. Using immunohistochemical methods, we assessed for HSP90 expression in 412 cases of non-Hodgkin's lymphoma. In B-cell lymphomas, HSP90 was moderately to strongly expressed in all cases of Burkitt's lymphoma (5/5, 100%), and in subsets of follicular lymphoma (17/28, 61%), diffuse large B-cell lymphoma (27/46, 59%), nodal marginal zone B-cell lymphoma (6/16, 38%), plasma cell neoplasms (14/39, 36%), small lymphocytic lymphoma/chronic lymphocytic leukemia (3/9, 33%), mantle cell lymphoma (12/38, 32%) and lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia (3/10, 30%). HSP90 was weakly expressed in six of 14 (43%) cases of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. In T-cell lymphomas, HSP90 was moderately to strongly expressed in subsets of anaplastic large-cell lymphoma (14/24, 58%; 9/12 ALK+ and 5/12 ALK-), precursor-T-cell lymphoblastic leukemia/lymphoma (20/65, 31%), unspecified peripheral T-cell lymphoma (8/43, 23%) and angioimmunoblastic T-cell lymphoma (2/17, 12%). HSP90 was weakly expressed in seven of 58 (12%) cases of mycosis fungoides. We conclude that HSP90 is commonly expressed in a subset of many types of B- and T-cell lymphoma. These data suggest that many lymphoma types are suitable targets for modulation of HSP90 activity, and that HSP90 inhibitors are a potential investigational therapy for lymphoma patients.
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PMID:Expression of heat-shock protein-90 in non-Hodgkin's lymphomas. 1605 52

Glucocorticoids are commonly used in the treatment of various lymphoid malignancies. In the present study, we show that dexamethasone (Dex) induced depolarization of mitochondrial membrane, release of cytochrome c and DNA fragmentation in a human follicular lymphoma cell line, HF28RA. New protein synthesis was required before Dex-induced mitochondrial changes, and the kinetics of the apoptotic events correlated with the upregulation of the Bim protein. Furthermore, we studied whether specific inhibitors of known survival pathways would potentiate Dex-induced apoptosis. Our results show that inhibition of PKC and ERK pathways had no effect on apoptosis. In contrast, inhibition of PI3-kinase or Akt markedly enhanced Dex-induced apoptosis. The enhancement was seen at the mitochondrial level, and the kinetics of apoptosis was notably accelerated. In addition, inhibition of PI3-kinase did not alter levels of Bax, Bcl-2, Bcl-X(L) or Bim proteins in mitochondria but caused translocation of the pro-apoptotic protein Bad to mitochondria. However, inhibition of PI3-kinase-Akt pathway and subsequent translocation of Bad to mitochondria did not induce apoptosis itself. Based on these results and our current understanding of Bim and Bad action, it seems that both proteins play a synergistic role in this process. Thus, these results indicate that inhibitors of PI3-kinase-Akt pathway might be combined in future with glucocorticoids to improve the treatment of lymphoid malignancies.
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PMID:Inhibition of PI3-kinase-Akt pathway enhances dexamethasone-induced apoptosis in a human follicular lymphoma cell line. 1630 71

Rituximab in combination with chemotherapy (immunochemotherapy) is one of the most effective treatments available for follicular lymphoma (FL). This study aimed to determine whether differences in gene expression in FL tissue correlate with outcome in response to rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy (R-CHOP). We divided 24 patients into long- [time to treatment failure (TTF) >35 months] and short-term (TTF <23 months) responders, and analysed the gene expression profiles of lymphoma tissue using oligonucleotide microarrays. We used a supervised learning technique to identify genes correlating with outcome, and confirmed the expression of selected genes with quantitative polymerase chain reaction (qPCR) and immunohistochemistry. Among the transcripts with a high correlation between microarray and qPCR analyses, we identified EPHA1, a tyrosine kinase involved in transepithelial migration, SMAD1, a transcription factor and a mediator of bone morphogenetic protein and transforming growth factor-beta signalling, and MARCO, a scavenger receptor on macrophages. According to Kaplan-Meier estimates, high EPHA1, and low SMAD1 and MARCO expression were associated with better progression-free survival (PFS). Immunohistochemistry showed that EphA1 was primarily localised in granulocytes. In addition, both EphA1 and Smad1 were expressed in vascular endothelia. However, no difference in vasculature was detected between long- and short-term responders. In a validation set of 40 patients, a trend towards a better PFS was observed among patients with high EphA1 expression. We conclude that gene expression in non-malignant cells contributes to clinical outcome in R-CHOP-treated FL patients.
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PMID:Differential gene expression in non-malignant tumour microenvironment is associated with outcome in follicular lymphoma patients treated with rituximab and CHOP. 1692 74


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