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)

Three receptor molecules, belonging to the class III of receptor tyrosine kinases, namely the receptors for colony-stimulating factor 1, CSF1R (product of the FMS proto-oncogene) and Steel factor, SLFR (product of the KIT proto-oncogene), as well as the recently identified FLT3/FLK2 gene product, appear to play distinct roles in normal hematopoietic differentiation. Their potential role in leukemic hematopoiesis has been approached by expression studies in hematopoietic malignancies, especially in acute leukemias of the myeloid and lymphoid lineages. We present here a review of available data, and discuss the possible significance and potential applications of these results.
Leuk Lymphoma 1994 Apr
PMID:The expression of FMS, KIT and FLT3 in hematopoietic malignancies. 751 7

An unusual hematologic neoplasia has been described recently in which the predominant clinical features include T-cell lymphoma, myeloid hyperplasia, and eosinophilia. The multilineage involvement in this disorder suggests transformation of a primitive stem cell. Abnormal karyotypes have been described in three such cases, including one case with t(8;13)(p11.2;q12) and a second case with t(8;13)(p23;q14). We report translocation of chromosomes 8 and 13 in lymph node karyotypes from two patients with this syndrome. Fluorescence in situ hybridization confirmed an identical translocation, t(8;13)(p11;q11-12), in lymphoma cells from each patient. The translocation breakpoints are of particular interest because the FLT3 receptor tyrosine kinase gene has been mapped 13q12. FLT3 is expressed highly in hematopoietic progenitor cells and in myeloid and lymphoid acute leukemias.
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PMID:Translocation t(8;13)(p11;q11-12) in stem cell leukemia/lymphoma of T-cell and myeloid lineages. 753 88

Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication in vitro (ED50 approximately 10 microM), undergoes extensive metabolism in vivo. Most of the orally administered drug undergoes opening of the dithiolethione ring, reduction, recyclization, and methylation to form 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine ("metabolite III"). We report here that metabolite III inhibits viral replication in vitro (ED50 approximately 25 microM) in acutely infected H9 and CEM T cell lymphoma cell lines. Although both metabolite III and oltipraz were able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in the chronically infected U1 promonocytic leukemia cell line, only metabolite III was able to inhibit phorbol-12-myristate-13-acetate-stimulated viral replication in chronically infected ACH-2 T cell lymphoma cells. The results with ACH-2 cells suggest that oltipraz inhibits an early stage of the viral life cycle, whereas metabolite III affects human immunodeficiency virus type 1 replication at a step distal to viral integration. This is consistent with the finding that oltipraz inhibits reverse transcriptase, whereas metabolite III does not. Although the mean ED50 for metabolite III in acutely infected peripheral blood mononuclear cells was 18 microM, the ED50 was below 5 microM in three of eight independent experiments. Studies of metabolite III in combination with oltipraz in acutely infected peripheral blood mononuclear cells demonstrated significant antiviral synergy. These results raise the possibility that the in vitro potency of oltipraz may underestimate its antiretroviral activity in vivo. Based on these results, the pharmacokinetics of oltipraz and metabolite III will be compared with the pharmacodynamic effects of orally administered oltipraz in a forthcoming phase I/II trial of oltipraz in patients with p24 antigenemia.
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PMID:Inhibition of human immunodeficiency virus type 1 replication by 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-a]pyrazine, an in vivo metabolite of oltipraz. 754 38

With diagnostic stereotactic biopsies in astrocytoma sometimes false results will be encountered. A false positive result is defined as a histological diagnosis which is afterwards proved to be untrue. Although this happens very seldom (1-2%) in characterizing the tumor type (e.g. astrocytoma versus lymphoma), there is a probability of undergrading in malignant astrocytomas due to regional heterogeneity in malignancy grade. The issue of 'sampling error' has been addressed by many authors. It was shown that undergrading in astrocytomas is a likely event in fibrillar astrocytomas that often show geographically distinct areas of well and poorly differentiated elements. In a recent study on histological grading versus genetic characterization of heterogeneous astrocytomas we published that low-grade areas within high-grade malignant astrocytomas have already the genetic features of high-grade malignancy. Therefore, particularly in stereotactic biopsies which contain relatively small samples of tumor tissue, this fact is of paramount importance. Undergrading may lead to withholding radiotherapy from the patient and to falsification of long-term survival results in series of so-called low-grade astrocytomas. We like to stress the importance of taking biopsies from different parts of the tumor, especially from parts with different density enhancement to contrast with CT scanning, and will discuss the technical advancements made in the genetic grading of astrocytomas. Particularly loss of heterozygosity of chromosome 10 and eventually amplification of the EGFR indicate a high grade of malignancy.
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PMID:Genetic versus histological grading in stereotactic biopsies. 762 52

The FLT3 gene encodes a receptor tyrosine kinase that is closely related to two well-known receptors, KIT and FMS, that regulate with their respective ligands, stem cell factor (SCF) and macrophage colony-stimulating factor (M-CSF), proliferation and differentiation of hematopoietic cells. The ligand for FLT3, FL, is active in both soluble and membrane-bound forms. We examined expression of FL and FLT3 mRNA in a panel of some 110 continuous human leukemia-lymphoma cell lines from all major hematopoietic cell lineages by Northern blot analysis. FLT3 mRNA is expressed primarily in pre-B cell lines, myeloid and monocytic cell lines whereas FL mRNA was detected in most cell lines from all cell lineages. Analysis of FLT3 receptor protein expression examined with a specific anti-FLT3 monoclonal antibody and flow cytometry in 17 cell lines confirmed the results obtained at the mRNA level. Forty of 110 cell lines displayed both receptor and ligand mRNA suggesting a possible autocrine or intracrine stimulation. In normal hematopoietic cells expression of FLT3 was reported to be associated with CD34 positivity, a cell surface marker of immature and precursor cells. No correlation between FLT3 and CD34 expression was found in the cell lines analyzed. These studies served to illustrate further the importance of the FL-FLT3 ligand-receptor system in the regulation of hematopoietic cells.
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PMID:Expression of FLT3 receptor and FLT3-ligand in human leukemia-lymphoma cell lines. 764 26

The translocation t(2;5)(p23;q35), discovered in CD30+ anaplastic large cell (ALC) lymphomas, creates a potentially oncogenic fusion gene, part of which is contributed by a novel tyrosine kinase, ALK. Absence of ALK expression from normal hematolymphoid cells provides a basis for the morphologic assessment of t(2;5). The distribution of the t(2;5) in ALC lymphomas and Hodgkin's disease (HD), as assayed by nonmorphologic methods, is controversial. We used in situ hybridization and/or immunohistology to show ALK gene products in 85 ALC lymphomas, 82 HD cases, 40 other lymphoproliferations, as well as in 6 HD- and 4 ALC lymphoma-derived cell lines. ALK gene products were restricted to t(2;5)-positive ALC lymphoma cell lines and tumor cells of 16 primary non-B cell, common-type ALC lymphomas. These were mainly from young patients with initial lymphonodal disease. ALK expression was not detectable in any other specimen, including all cases of HD and HD-like type ALC lymphoma as well as secondary ALC lymphomas. Full congruence was noted for labeling results obtained with both methods. In agreement with cytogenetic analyses, but at variance with recently published studies, ALK gene expression distinguishes a subset of ALC lymphomas from other CD30+ lymphomas, including HD. The results do not support concepts attributing a significant role to the t(2;5) in the development of HD.
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PMID:ALK gene products in anaplastic large cell lymphomas and Hodgkin's disease. 765 1

Point mutations at codons 301 and 969 of the FMS proto-oncogene have been reported in both myelodysplasia (MDS) and acute myeloid leukaemia (AML). We report here the incidence of such mutations in patients at risk of developing secondary MDS and AML. Peripheral blood DNA from 70 patients in remission from lymphoma was screened for mutations by oligonucleotide (ONH) using mutant specific probes. Codon 969 mutations were detected in 11 of the 70 (15.7%) cases. No codon 301 mutations were detected. Five of these mutations were confirmed using an independent technique (single nucleotide primer extension analysis, SNPE) and a further mutation was detected in a single patient using single-stranded conformational polymorphism analysis (SSCP). No codon 969 mutations were detected in 62 lymphoma biopsy specimens from these patients or from three patients with detectable FMS mutations where pre-therapy marrow was investigated by ONH. No mutations at either codons 301 or 969 were detected by ONH in 61 normal controls. Somatic mutations at codon 969 of the FMS gene occur commonly following cytotoxic therapy for lymphoma and their detection indicates the presence of a clonally expanded population of abnormal cells.
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PMID:FMS mutations in patients following cytotoxic therapy for lymphoma. 776 31

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 case of a 36-year-old woman is presented. She had a voluminous tumour inside the 1/3 average part of the right thigh at 12 cm from the inguinal region. Apart from some local pains, she had a normal haematological formula, normal spleen, liver and lymph nodes. As the tumour of 5.5 x 5 x 4.5 cm was well incapsulated between the sartorius muscle and the great adductor tendon it was easily extirpated and presented a whitish-light yellow section. The histological cellular aspect was pleiomorphic with round, ovalar cells; some were big and clear cells of centroblast-type with several mitoses and giant multinucleated cells and collagenic bundles in between. The nodular Hodgkin sclerosis is not confirmed immunohistochemically because of the negative reaction for antigen Kil (CD30) so that the diagnosis was lymphoma with lymphoma with big B cells by CD20 reaction. We also found positive T cells at CD43 that might be reactive lymphocytes. The tumour ranks a rare malignant lymphoma and for the first time, an extraganglionar lymphoma in thigh was found. We have not met such a location in the literature.
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PMID:Voluminous solitary non-Hodgkin extraganglionary lymphoma of thigh. 784 84

Although cytogenetic data suggest that the t(2;5)-(p23;q35) translocation occurs in many cases of CD30+ lymphomas, the exact frequency of this event is still unknown. To clarify this issue and its epidemiological characteristics, we examined 37 formalin-fixed, paraffin-embedded specimens of CD30+ lymphomas from the United States and Hong Kong by reverse transcriptase-polymerase chain reaction (RT-PCR) for the status of the NPM and ALK genes, which are typically juxtaposed by the t(2;5) translocation. Thirty-four cases were classified as anaplastic large cell lymphomas (ALCL), 2 cases as non-anaplastic large cell lymphomas (LCL), and 1 case as the small cell variant of CD30+ lymphoma. The t(2;5) translocation was detected in 6 cases (16%), including 3 of 18 American patients and 3 of 19 cases from Hong Kong. All cases had a 185-bp NPM RT-PCR product as detected by Southern blot analysis, indicating adequate preservation of mRNA. The 6 positive cases were among 4 of 34 adult lymphomas, as compared with 2 of 3 childhood cases. Five of 17 T-lineage cases were t(2;5)-positive, compared with 1 of 15 B-lineage cases and none of the 5 null-cell or mixed lineage cases. Our results therefore show that t(2;5) occurs at a low frequency among CD30+ lymphomas, at least in our adult-dominated series.
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PMID:Low frequency association of the t(2;5)(p23;q35) chromosomal translocation with CD30+ lymphomas from American and Asian patients. A reverse transcriptase-polymerase chain reaction study. 785 44


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