Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcriptional enhancers of replication-competent mouse C-type retroviruses are potent determinants of the distinct disease-inducing phenotypes of different viral isolates and can also strongly influence the incidence and latent period of disease induction. To study the contribution of individual protein-binding sites to viral pathogenicity, we introduced mutations into each of the known nuclear factor-binding sites in the enhancer region of the Moloney murine leukemia virus and injected viruses with these mutations into newborn NFS mice. All viruses induced disease. Viruses with mutations in both copies of the leukemia virus factor a (LVa) site, leukemia virus factor c (LVc) site, or in just the promoter proximal copy of the glucocorticoid response element (GRE) had a latent period of disease onset and disease specificity indistinguishable from that of the wild-type Moloney virus. Viruses with mutations in two or three of the GREs, in both copies of the leukemia virus factor b (LVb) site, in two of the four nuclear factor 1 (NF1) consensus motifs, or in both copies of the conserved viral core element showed a significant delay in latent period of disease induction. Strikingly, viruses with mutations in the core element induced primarily erythroleukemias, and mutations in the LVb site also resulted in a significant incidence of erythroleukemias. These and other genetic and biochemical studies suggest models for how subtle alterations in the highly conserved structure of mouse C-type retrovirus enhancers can produce a dramatic effect on disease specificity.
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PMID:Mutation of the core or adjacent LVb elements of the Moloney murine leukemia virus enhancer alters disease specificity. 233 44

Previous studies have shown that carboxyl-terminal mutation of pp60c-src can activate its transforming ability. Conflicting results have been reported for the transforming ability of pp60c-src mutants having only mutations outside its carboxyl-terminal region. To clarify the effects of such mutations, we tested the activities of chimeric v(amino)- and c(carboxyl)-src (v/c-src) proteins at different dosages in NIH 3T3 cells. The focus-forming activity of Rous sarcoma virus long terminal repeat (LTR)-src expression plasmids was significantly reduced when the v-src 3' coding region was replaced with the corresponding c-src region. This difference was masked when the Rous sarcoma virus LTR was replaced with the Moloney murine leukemia virus LTR, which induced approximately 20-fold more protein expression, but even focus-selected lines expressing v/c-src proteins were unable to form large colonies in soft agarose or tumors in NFS mice. This suggests that pp60c-src is not equally sensitive to mutations in its different domains and that there are at least two distinguishable levels of regulation, the dominant one being associated with its carboxyl terminus. v/c-src chimeric proteins expressed with either LTR had high in vitro specific kinase activity equal to that of pp60v-src but, in contrast, were phosphorylated at both Tyr-527 and Tyr-416. Total cell protein phosphotyrosine was enhanced in cells incompletely transformed by v/c-src proteins to the same extent as in v-src-transformed cells, suggesting that the carboxyl-terminal region may affect substrate specificity in a manner that is important for transformation.
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PMID:v-src mutations outside the carboxyl-coding region are not sufficient to fully activate transformation by pp60c-src in NIH 3T3 cells. 245 Nov 22

NFS-60 cells were previously obtained from leukemia cells that were infected with the Cas-Br-M murine leukemia virus in vivo. We examined the proliferation and differentiation capacity of NFS-60 cells in the presence of native and recombinant (r) interleukin 3 (IL-3), recombinant granulocyte colony-stimulating factor (rG-CSF), recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), and r-erythropoietin (Ep) using methylcellulose culture methods. This cell line was able to form colonies in response to each hemopoietic factor, but colony formation was rarely seen in their absence. Some populations of NFS-60 cells could differentiate into neutrophils and macrophages in the presence of IL-3 and GM-CSF. Moreover, in the presence of Ep, this cell line formed well-hemoglobinized colonies as well as nonerythroid colonies. In the presence of G-CSF, NFS-60 cells remained in the promyelocytic state. Electron microscopic studies confirmed these morphologies. A single-cell transfer experiment demonstrated that neutrophils, macrophages, and erythroblasts were derived from a single cell. It is concluded that the NFS-60 cell line is a factor-dependent, bipotential hemopoietic cell line.
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PMID:Bipotential murine hemopoietic cell line (NFS-60) that is responsive to IL-3, GM-CSF, G-CSF, and erythropoietin. 245 92

Two patients with acute myelomonocytic leukemia (AMMoL) were tested to determine whether or not their cells produced granulocyte colony-stimulating factor (G-CSF). Using the NFS-60 bioassay method, relatively high levels of G-CSF were demonstrated in the serum pre-treated with acid-dialysis and in the media conditioned by leukemia cells. Northern blot analysis for G-CSF using cDNA as a probe revealed that G-CSF production was increased at the mRNA level in the cells. No rearrangement at the DNA level, however, was observed by genomic Southern analysis. Our data indicate that the leukemic cells in AMMoL probably have the capacity to synthesize and secrete G-CSF.
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PMID:Production of granulocyte colony-stimulating factor by acute myelomonocytic leukemia cells. 246 97

[3H]thymidine uptake by NFS-60 cells in microcultures was found to increase in a linear fashion with the increasing doses of purified recombinant human granulocyte colony-stimulating factor (rhG-CSF). Such increases were found neither with rhG-CSF samples pretreated with rabbit anti-rhG-CSF serum nor with other human colony-stimulating factors such as granulocyte-macrophage colony-stimulating factor (hGM-CSF) or macrophage colony-stimulating factor (hM-CSF). Based on these findings, sera from normal persons and patients with severe infections or various hematological disorders were tested after dialysis using this system in order to determine whether G-CSF levels in sera can be estimated or not. In ten normal persons, five patients with acute myelogenous leukemia (AML M1, M2, and M3), five with myelodysplastic syndrome, and four with chronic myelogenous leukemia, no increases in [3H]thymidine uptake were found within the dose range of 0.4 microliters to 50 microliters. In contrast, linear dose responses parallel to a G-CSF standard curve were observed in one patient with a severe bacterial infection, four with aplastic anemia, two with acute myelomonocytic leukemia (AMMoL) (M4), and two with idiopathic neutropenia tested. From the standard curve, the probable levels of G-CSF were calculated as follows: approximately 200 pg/ml with infection, 130-220 pg/ml with aplastic anemia, 150 and 200 pg/ml with AMMoL, and 1120 and 1200 pg/ml with idiopathic neutropenia. The activities of sera were reduced by the anti-rhG-CSF serum pretreatment in the same way as documented in the case of rhG-CSF. Furthermore, the level in a patient with a severe infection became undetectable soon after elimination of the infection and blood neutrophil counts had returned to normal. These findings indicate that the microbioassay system will be useful for measuring circulating G-CSF levels which would fluctuate in accord with requirements for stimulating neutrophil production or with abnormal production of hG-CSF.
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PMID:A new bioassay for human granulocyte colony-stimulating factor (hG-CSF) using murine myeloblastic NFS-60 cells as targets and estimation of its levels in sera from normal healthy persons and patients with infectious and hematological disorders. 246 30

Purified recombinant granulocyte colony stimulating factor (G-CSF) and interleukin-6 (IL-6) stimulated the formation of similar numbers of colonies in cultures of normal mouse marrow cells. LIF and IL-6 induced comparable differentiation in clonal cultures of murine M1 leukemic cells and exhibited enhanced actions in combination. However, LIF was 16-25-fold more active than IL-6. Induction of differentiation in M1 leukemic colonies by both LIF and IL-6 was enhanced by the addition of G-CSF or M-CSF but not by GM-CSF or Multi-CSF. Both G-CSF and IL-6, but not LIF, were able to induce differentiation in murine WEHI-3B leukemic colonies, but G-CSF was 10-fold more efficient than IL-6. Both G-CSF and IL-6 were able to stimulate the proliferation of cells of the NFS-60 continuous cell line, but G-CSF was 30-fold more efficient. M1 cells constitutively produced low levels of IL-6 and production was enhanced by LIF, but the general characteristics of the actions of LIF, IL-6, and G-CSF suggested that each operates independently as a direct differentiation inducer of leukemic cells. The similarities in the biology and actions of G-CSF, LIF, and IL-6 suggest that they may be designed to exhibit coordinated biological functions in certain situations.
Leukemia 1989 May
PMID:Actions and interactions of G-CSF, LIF, and IL-6 on normal and leukemic murine cells. 246 11

A replication-defective murine retroviral construct, termed pME26, was generated by inserting avian gag-myb-ets sequences derived from the cloned avian acute leukemia virus E26 into an Abelson murine leukemia virus-derived retroviral vector. ME26 virus can be rescued efficiently from transfected NIH 3T3 cells by replicating murine leukemia viruses. Either pME26-transfected nonproducers or ME26 virus-infected NIH 3T3 cells expressed a 135-kilodalton fusion protein (p135) which was detectable by immunoprecipitation with antiserum directed against avian leukemia virus p27gag, myb or ets oncogene protein, or murine leukemia virus p15gag and was principally localized in the nucleus. NIH 3T3 cells infected with ME26 exhibited morphological alterations and increased proliferation in reduced serum and formed small colonies in agar suspension. Discrete foci could be readily recognized in cells maintained in a defined medium containing 0.03 to 0.1% calf serum. In newborn NFS/N mice, ME26 induced a significantly higher mortality and incidence of erythroid and myeloid leukemias. Analysis of a series of mutants affecting the expression of various portions of p135 indicated that the v-ets gene acts to mitogenically stimulate the proliferation of NIH 3T3 fibroblasts and reduces or abolishes their serum dependence. These properties provide an assay system to study functions of the ets gene family.
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PMID:Properties of a murine retroviral recombinant of avian acute leukemia virus E26: a murine fibroblast assay for v-ets function. 253 27

Using in vitro protein binding and in vivo functional studies, we have identified novel regulatory sequences near the 5' end of murine leukemia virus (MuLV) long terminal repeats (LTRs). These sequences are highly conserved in all MuLV LTRs as well as in feline leukemia virus and gibbon ape leukemia virus LTRs. In this upstream conserved region (UCR), gel retardation assays detected two overlapping but distinct binding sites (UCR-U and UCR-L) for nuclear proteins (UCRF-U and UCRF-L). Three lines of evidence suggest a negative regulatory role for the UCR in viral transcription: (i) an inverse correlation was found between MuLV transcripts and nuclear proteins binding the UCR in the spleens of five different mouse strains; (ii) in vivo treatment of NFS mice with lipopolysaccharide resulted in the induction of splenic viral transcripts and the concomitant disappearance of UCR-binding proteins; and (iii) in mouse L cells transfected with an MuLV LTR linked to the chloramphenicol acetyltransferase (CAT) gene, cotransfected UCR oligonucleotides increased CAT expression, presumably by competing for inhibitory trans-acting factors.
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PMID:Negative control region at the 5' end of murine leukemia virus long terminal repeats. 254 Apr 25

A group of mink cell focus-forming (MCF) viruses was derived by inoculation of NFS/N mice with Moloney murine leukemia virus (Mo-MuLV 1387) and was compared to a similarly derived group of MCF viruses from mice inoculated with Friend MuLV (Fr-MuLV 57). Antigenic analyses using monoclonal antibodies specific for MCF virus and xenotropic MuLV envelope proteins and genomic structural analyses by RNase T1-resistant oligonucleotide finger-printing indicated that the Moloney and Friend MCF viruses arose by recombination of the respective ecotropic MuLVs with different endogenous retrovirus sequences of NFS mice.
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PMID:Friend and Moloney murine leukemia viruses specifically recombine with different endogenous retroviral sequences to generate mink cell focus-forming viruses. 257 66

The functional role of a mutant RAS gene in immortal myeloid cell proliferation was examined in a fastidious interleukin-3 (IL-3) dependent cell line (NFS/N1.H7) formed by forced proliferation in IL-3 of marrow cells of the NFS/N mouse. The NFS/N1.H7 cell line was strictly dependent upon IL-3 for growth, and the cell line could be activated by phorbol esters (PMA) to augment IL-3 dependent proliferation, but when pKC was downregulated, diminished IL-3 proliferative response resulted. Transfection (electroporation) of the T24 RAS-containing vector pAL8 to NFS/N1.H7 led to clones (H7 NeoRas.F3, H7 NeoRas.E2) that had incorporated the entire 6.6 Kb human mutant H-RAS genome. The mutant RAS-containing clones demonstrated greater proliferation than parent cells or cells containing a control (neo-resistance) vector over a range of suboptimal IL-3 does and in optimal IL-3 concentrations had a faster doubling rate than parent cells. The clone H7 NeoRas.F3 was studied biochemically, and found to constitutively form 3-fold more 3H-diacylglycerol than the parent cell line upon exposure to 3H-glycerol. PMA could partially repair the proliferative defect of NFS/N1.H7 compared to the RAS-expressor. These studies affirm a secondary, accelerating role for a mutant RAS gene product acting through pKC to promote clonal expansion of immortal myeloid cells stimulated by IL-3.
Leukemia 1989 Sep
PMID:A mutant RAS gene acts through protein kinase C to augment interleukin-3 dependent proliferation in a fastidious immortal myeloid cell line. 266 57


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