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)

Antileukemia sera with "directed" specificity are produced by immunization of rabbits with mouse leukemia cells admixed with normal antigen blocking (NAB) serum. Addition of NAB serum to the leukemia cells inhibits production of antibodies to normal cell components and directs specificity toward leukemia cell antigens. The resulting antileukemia serum (ALK-NABS) was not sufficiently potent to produce more than moderate therapy in the standard L1210 leukemia therapy assay. When given together with noncurative doses of cyclophosphamide (CTX), ALK-NABS acts synergistically. It is most effective when given early after injection of the leukemia cells and prior to injection of CTX. Daily repeated injections of a given dose are more effective than a single injection of that dose. Most important, small doses of ALK-NABS produce a significant prolongation of lifespan in conjunction with CTX. Results of therapy for BW-A leukemia with ALK-NABS in conjunction with CTX were negative.
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PMID:Passive immunotherapy for mouse leukemias with antisera of "directed" specificity: synergism with the action of cyclophosphamide. 92 53

We studied 41 patients with myelodysplastic syndromes or acute myeloid leukemia to assess the presence of point mutations in the human FMS gene (M-CSF receptor). Using the polymerase chain reaction and hybridization of oligonucleotide probes to the amplified sequences, we have detected mutations in eight of 41 patients, at codons 301 and 969. In vitro work has highlighted mutations at these codons as being oncogenic. We now report the detection of potentially activating mutations of the human FMS gene in vivo. The consequence of these mutations in the multistep pathogenesis of myeloid malignancy and their relevance to prognosis remains to be determined.
Leukemia 1990 Jul
PMID:Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia. 214 47

The in vitro action of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D arabinofuranosylcytosine (ara-C) was studied on the human leukemia cell line U 937. Parameters investigated included monitoring of transcript levels of the proto-oncogenes C-MYC, C-FOS, and C-FMS, and analysis of nitroblue tetrazolium (NBT) reduction and of surface expression of the C3 bi receptor. Furthermore clonal proliferation of U 937 cells was assessed in soft agar cultures. The results indicate that both agents have only little effects on U 937 cells when acting alone. When combined in culture, however, they synergize to induce monocytic differentiation of U 937 cells as disclosed by significant increase of cells capable of reducing NBT and displaying surface C3 bi receptor that was accompanied by reduction of clonogenicity in colony assays. Induction of differentiation and inhibition of proliferation of U 937 cells was preceded by downregulation of transcript levels of C-MYC, increase of C-FOS mRNA, and induction of accumulation of C-FMS mRNA. By sequential use of LIF and ara-C we also demonstrate that the basis of synergism of both agents does not involve mechanisms at the level of receptor ligation but that synergism may be initiated by complementary intracellular metabolic cascades.
Leukemia 1990 Sep
PMID:Synergistic effect of recombinant human leukemia inhibitory factor (LIF) and 1-beta-D-arabinofuranosylcytosine (Ara-C) on proto-oncogene expression and induction of differentiation in human U 937 cells. 214 31

By in situ chromosomal hybridization, the GM-CSF and FMS genes were localized to human chromosome 5 at bands q23 to q31, and at band 5q33, respectively. These genes encode proteins involved in the regulation of hematopoiesis, and are located within a chromosome region frequently deleted in patients with neoplastic myeloid disorders. Both genes were deleted in the 5q-chromosome from bone marrow cells of two patients with refractory anemia and a del(5)(q15q33.3). The GM-CSF gene alone was deleted in a third patient with acute nonlymphocytic leukemia (ANLL) who has a smaller deletion, del(5)(q22q33.1). Leukemia cells from a fourth patient who has ANLL and does not have a del(5q), but who has a rearranged chromosome 5 that is missing bands q31.3 to q33.1 [ins(21;5)(q22;q31.3q33.1)] were used to sublocalize these genes; both genes were present on the rearranged chromosome 5. Thus, the deletion of one or both of these genes may be important in the pathogenesis of myelodysplastic syndromes or of ANLL.
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PMID:Evidence for the involvement of GM-CSF and FMS in the deletion (5q) in myeloid disorders. 348 37

The discovery of EGFR gene amplification in glioblastoma multiforme has prompted interest in experimental therapies to target the receptor on brain tumor cells. To develop an animal model for in vivo study of such strategies, we transfected C6 glioma cells with a plasmid containing the neomycin resistance gene and the human EGFR gene under the control of the glucocorticoid-inducible MMTV promoter. Following selection with G418, individual clones that expressed EGFR at high levels were selected. Kinetics of EGF binding fit a dual site model indicating the presence of both high (KA = 2.5 x 10(9) M-1) and low (KA = 3.3 x 10(7) M-1) affinity receptors. To assess growth in vivo, graded numbers of either wild-type or transfected cells were implanted into the brains of CD Fischer 344 rats. No differences in survival were observed between groups of animals injected with either wild-type or transfected cells at inocula of 10(3) or 10(4) respectively. In addition, one-third of animals (7/21) challenged with 10(5) or 10(6) transfected cells survived > 50 days compared to 0% of animals (0/12) challenged with 10(5) or 10(6) wild-type cells. Such an effect suggests greater immunogenicity of transfected cells, but only at the larger inocula. Since C6 glioma cells will grow in both outbred and inbred strains, our model should have a number of applications including the in vivo study of EGFR targeting for glioma therapy.
Leukemia 1995 Oct
PMID:The effect of epidermal growth factor receptor (EGFR) expression on in vivo growth of rat C6 glioma cells. 747

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.
Leukemia 1995 Aug
PMID:Expression of FLT3 receptor and FLT3-ligand in human leukemia-lymphoma cell lines. 764 26

Multiple myeloma (MM) is defined as a tumoral expansion of plasma cells occurring in the bone marrow and sometimes in the peripheral blood (plasma-cell leukemia, PCL). Many reports have demonstrated a clonal expansion of B cells bearing the same idiotypic determinants as the myeloma protein (idiotypic B cells) in MM, suggesting that they could belong to the malignant clone. In order to investigate whether the B-cell population is a malignant component or not, either in the peripheral blood of patients with PCL or in the bone marrow of patients with MM, we derived B-cell lines by infecting, with the Epstein-Barr virus (EBV), cultures in limiting dilution of mononuclear cells from six patients. A limiting dilution culture was used to prevent the elimination of slowly proliferating clones by the more rapidly dividing ones, and thus to get the most exact representation of the B-cell repertoire of these patients. The cloning efficiency of the EBV-infected cells was similar in patients and healthy individuals (range: 1 in 100 to 1 in 1650 B cells). All of the clones obtained from a single patient exhibited different clonal immunoglobulin gene rearrangements (IGR), proving the validity of our cloning technique. No tumoral clones (61 clones analysed) showed the IGR pattern specific of autologous myeloma cells. These results indicate that malignant plasma cells cannot be immortalized with EBV. These results show that, if malignant B cells (pre-switch or post-switch) exist, they could be present only in a minor population, and the corollary of this is that there is a major population of non-malignant B cells in the sites of tumoral proliferation of patients with MM. This is remarkable in view of numerous reports showing a profound defect of the polyclonal B lymphopoiesis in these patients, and even an absence of B lymphocytes. Thus, these results challenge the existence of a major compartment of malignant idiotypic B cells and favor the hypothesis of non-malignant B cells sharing cross-reactive idiotypes with the autologous myeloma protein.
Leukemia 1993 Apr
PMID:Analysis of the B-cell compartment in plasma cell leukemia and multiple myeloma: immunoglobulin gene rearrangement of EBV-infected B-cell lines. 768 18

The KIT proto-oncogene encodes a tyrosine kinase receptor which plays a critical role in haemopoiesis. We have screened genomic DNA from bone marrow mononuclear cells of 46 patients with myelodysplasia (MDS) for mutations/deletions of exons 6, 13, 17, and 21 of the KIT gene (stem cell factor receptor) using polymerase chain reaction (PCR), polyacrylamide gel electrophoresis, and autoradiography to detect single-stranded conformational polymorphisms (SSCP). These exons include positions analogous to those mutated in the FMS gene (colony-stimulating factor-1 receptor) in myelodysplastic syndrome (MDS) and mutated/deleted in the Dominant White Spotting mouse (W locus) which results in macrocytic anaemia. Two different gel running conditions were used for each exon. Polymorphisms were identified only at 4 degrees C in exon 17 (three out of 44 MDS samples and two of 21 DNA samples from normal subjects), and in the non-coding region of exon 21 (five out of 34 MDS samples and seven out of 19 normals). Direct sequencing identified a G to A base change at nucleotide 3169 within exon 21, and a C to T change at position 2415 in exon 17. No conformational changes suggestive of mutations or deletions have been found to date, although we cannot rule out low frequency clonal abnormalities undetectable by our method, which has a sensitivity in our hands of approximately 5%. Polymorphisms occur frequently in the KIT gene. Together with this study, a total of five have been described.
Leukemia 1993 Nov
PMID:Two new polymorphisms but no mutations of the KIT gene in patients with myelodysplasia at positions corresponding to human FMS and murine W locus mutational hot spots. 769 8

The FMS proto-oncogene encodes a polypeptide growth factor receptor expressed on the cell surface of monocytes and B lymphocytes within the haematological system. Mutations of the FMS gene at codons 301 and 969 have been detected in a number of haematological disorders. Mutations at these codons are thought to be important in the pathogenesis of leukaemia in cells expressing a mutant receptor. Following our finding that the colony stimulating factor-1 receptor (CSF-1R) was expressed on B cells, we have assessed DNA from 17 patients with B-cell chronic lymphocytic leukaemia (CLL), 15 with acute lymphoblastic leukaemias (ALL), two samples from patients with B-cell non-Hodgkin's lymphoma (B-NHL), and 20 haematologically normal individuals for the presence of C-terminal mutations of the FMS gene. Using single stranded conformational polymorphism analysis (SSCP), a single band shift was detected resulting from a nucleotide insertion at codon 965 in the DNA isolated from a patient with B-NHL. These results indicate that mutations of the FMS gene in this region are rare in B-cell malignancy but may contribute to the pathogenesis of leukaemias and lymphomas in a small subset of patients. However, the presence of other mutations not detected using this type of analysis cannot be excluded.
Leukemia 1995 Jan
PMID:A C-terminal FMS mutation in a patient with B-cell malignancy. 784 11

Patients who have received cytotoxic therapy for primary neoplastic disease are at an increased risk of developing secondary (therapy-related) acute myeloid leukaemia (AML) or myelodysplasia (MDS). RAS and FMS mutations have been observed in patients with AML and MDS. It has been suggested that the mutational status within these genes may be predictive of early secondary leukaemic disease. In this study we have screened 50 haematologically normal patients in complete remission from childhood acute lymphoblastic leukaemia (ALL) for activating point mutations in the RAS and FMS proto-oncogenes. Such patients may be considered at risk of therapy-related disease. Codons 12, 13 and 61 were screened in RAS and codon 969 in FMS using the polymerase chain reaction (PCR) followed by oligonucleotide hybridization (ONH). Three of the 50 patients (6%) were found to harbour N12 RAS mutations. One of these three patients (2%) had both a N12 RAS and FMS 969 mutation. Upon sequencing the RAS mutations, substitutions of serine, cysteine and aspartic acid for glycine were identified. The FMS 969 mutation was also confirmed, by sequencing, as a histidine substitution. RAS mutations were not detected in presentation samples indicating that these lesions have been somatically acquired presumably subsequent to cytotoxic therapy for the primary disease. Continued follow-up of these patients may indicate a role for these mutations in the development of secondary malignancies.
Leukemia 1995 Mar
PMID:RAS and FMS mutations following cytotoxic therapy for childhood acute lymphoblastic leukaemia. 756 28


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