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)

Dipyridamole (DPM) enhanced sensitivity to doxorubicin (DOX) in a human leukemia cell line that was already relatively sensitive to this agent. Using an immunofluorescence technique, we determined the localization of nucleophosmin (protein B23) in HL-60 cells after incubation with DOX in the absence and presence of DPM. Bright nucleolar fluorescence was observed in control HL-60 cells. The addition of DOX (0.1-0.25 micrograms/ml) in the culture system resulted in time- and dose-dependent induction of nucleophosmin translocation from the nucleolus to nucleoplasm and inhibition of cell growth. DPM (5 microM) alone had no effect on nucleophosmin translocation and inhibition of cell growth. However, the addition of DPM to the cells enhanced DOX-stimulated translocation of nucleophosmin. There was a good correlation between the DPM enhancement of DOX-induced nucleophosmin translocation and the increased inhibition of cell growth. The cell number decreased to a greater extent within a shorter time period under treatment with DOX in the presence of DPM. Short exposure (0.5 hr) of HL-60 cells to DOX induced dose-response nucleophosmin translocation and cell growth inhibition. Such effects of a short exposure to DOX were also enhanced by DPM (5 microM) included in the fresh medium after removal of DOX. This was in agreement with the observation that DPM could increase the cellular DOX by inhibiting the drug efflux from the cells. These results demonstrate that DPM, being able to increase and retain the intracellular levels of DOX, can markedly enhance the cytotoxicity of DOX, and suggest possible clinical application. "Nucleophosmin translocation", as observed by immunofluorescence, could be useful in determining the efficacy of combinations of DOX and DPM in cancer chemotherapy.
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PMID:Dipyridamole enhancement of doxorubicin-induced translocation of nucleophosmin and inhibition of cell growth in HL-60 cells. 191 61

Mouse leukemia (P388) cells were incubated in cell culture medium containing nitrogen mustard [2-chloro-N-(2-chloroethyl)-N-methylethanamine] for 4 h. The nucleophosmin immunoband with a molecular weight of 37,000 (p37; other molecular weights are similarly designated) was observed in both control and nitrogen mustard-treated cells. Three additional immunobands with molecular weights of 80,000 (p80), 120,000 (p120), and 230,000 (p230) were identified in the drug-treated cells. The same results were observed with melphalan, but were not detected when mitomycin C, cis-platinum, Adriamycin, or actinomycin D were used. Treatments with DNase and RNase did not alter the molecular weights of these immunobands. These results indicate that the cross-linked products of nucleophosmin were not linked to DNA or RNA. The pI of p80, p120, and p230 is 5.1, which is the same as that of nucleophosmin (p37). The iodinated tryptic peptide map of p80 is identical to that of nucleophosmin. This result indicates that p80 is a dimer cross-linked by nitrogen mustard. The p80 and p120 immunobands were observed in Novikoff hepatoma and in hypertrophic rat liver, but were not detected in normal liver under the same conditions. These results indicate that tumor or proliferating cells have hexameric nucleophosmins which can be cross-linked by nitrogen mustards.
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PMID:Cross-linkage of nucleophosmin in tumor cells by nitrogen mustard. 272 Jun 80

Changes in topoisomerase I (topo I) levels and localization were examined during the course of granulocytic maturation in vitro and in vivo. Western blotting revealed that granulocytic maturation in DMSO-treated HL-60 human leukemia cells was accompanied by a 5-fold decrease in topo I polypeptide content. Consistent with this result, 3- to 5-fold higher concentrations of the topo I poison camptothecin were required to stabilize topo I-DNA adducts in DMSO-treated HL-60 cells compared to untreated cells. Northern blotting revealed that these changes occurred without any decrease in topo I message. Immunolocalization studies revealed that these quantitative changes were accompanied by redistribution of topo I away from the nucleoli, where it was prominently accumulated in untreated HL-60 cells, to a more uniform nuclear distribution in DMSO-treated cells. Similar changes occurred during granulocytic maturation in human marrow in vivo. Western blotting revealed that topo I levels in normal progranulocytes were 50% as high as those in HL-60 cells, levels in metamyelocytes were 35% as high as HL-60 cells, and levels in peripheral blood granulocytes were 5% as high as HL-60 cells. Two other polypeptides that are concentrated in nucleoli, poly(ADP-ribose) polymerase and B23/nucleophosmin, also decreased during the course of granulocytic maturation. These changes were accompanied by an alteration in topo I localization similar to that observed in HL-60 cells during the course of granulocytic maturation. Conversely, treatment of human lymphocytes with the mitogenic lectin concanavalin A resulted in a 3-fold increase in topo I polypeptide content concomitant with a prominent increase in the amount of nucleolar antigen. These observations not only provide a context for understanding the recent observation that topo I levels are higher in human leukemia specimens than in normal marrow but also raise the possibility that elevated topo I levels in other cells might reflect alterations in nucleolar structure and function.
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PMID:Changes in topoisomerase I levels and localization during myeloid maturation in vitro and in vivo. 788 18

A t(3;5)(q25.1;q34) chromosomal translocation associated with myelodysplastic syndrome and acute myeloid leukemia (AML) was found to rearrange part of the nucleophosmin (NPM) gene on chromosome 5 with sequences from a novel gene on chromosome 3. Chimeric transcripts expressed by these cells contain 5' NPM coding sequences fused in-frame to those of the new gene, which we named myelodysplasia/myeloid leukemia factor 1 (MLF1). RNA-based polymerase chain reaction analysis revealed identical NPM-MLF1 mRNA fusions in each of the three t(3;5)-positive cases of AML examined. The predicted MLF1 amino acid sequence lacked homology to previously characterized proteins and did not contain known functional motifs. Normal MLF1 transcripts were expressed in a variety of tissues, most abundantly in testis, ovary, skeletal muscle, heart, kidney and colon. Anti-MLF1 antibodies detected the wild-type 31 kDa protein in K562 and HEL erythroleukemia cell lines, but not in HL-60, U937 or KG-1 myeloid leukemia lines. By contrast, t(3;5)-positive leukemia cells expressed a 54 kDa NPM-MLF1 protein, but not normal MLF1. Immunostaining experiments indicated that MLF1 is normally located in the cytoplasm, whereas NPM-MLF1 is targeted to the nucleus, with highest levels in the nucleolus. The nuclear/nucleolar localization of NPM-MLF1 mirrors that of NPM, indicating that NPM trafficking signals direct MLF1 to an inappropriate cellular compartment in myeloid leukemia cells.
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PMID:The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. 857 Feb 4

We have previously detected by immunofluorescent assay that the cellular localization of nucleophosmin/B23 (NPM) shifts from the nucleolus to the nucleoplasm (NPM-translocation) after exposure of cells to multiple agents. In order to improve the quantification of the NPM-translocation, we have developed a digital imaging technique. Human Lo leukemia cells, MCF-7 breast carcinoma cells, and fresh human leukemia cells were exposed to anthracyclines or actinomycin D for 4 h. The degree of NPM-translocation was determined and presented as the localization index (LI). Control cells had a LI of about 10, which indicates that the majority of NPM was localized in nucleoli. The LI for drug-treated cells decreased in a dosage- and time-dependent manner. The effect of two classes of anthracycline (daunomycin and aclacinomycin A) and different types of intercalators (daunomycin and actinomycin D) had additive effects on induction of NPM-translocation. The imaging procedure was easily applied to fresh leukemia cells, thus providing useful information regarding drug effects on cancer cells.
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PMID:Quantitation of the nucleophosmin/B23-translocation using imaging analysis. 862 Apr 41

Interferon Regulatory Factor-1 (IRF-1) acts as a transcriptional activator in interferon system and as a tumor suppressor. The loss of functional IRF-1 has been shown in approximately 30% of patients with myelodysplastic syndrome (MDS) and overt leukemia from MDS. Here we report an alternative mechanism of inactivation of IRF-1 activity. We identified an IRF-1 binding protein (IRF-BP). Protein sequencing revealed that IRF-BP was identical to nucleophosmin (NPM), a nucleolar phosphoprotein. Functional analysis showed that IRF-BP inhibited DNA-binding and transcriptional activity of IRF-1. Moreover when we examined several leukemia samples, the level of IRF-BP mRNA was increased. These results are consistent with the hypothesis that IRF-BP binds to IRF-1, and that overexpression of IRF-BP in leukemias leads to escape from IRF-1-regulated growth control. This hypothesis was also supported by the fact that overexpression of IRF-BP in NIH 3T3 cells rendered cells transformed.
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PMID:[Identification and analysis of IRF-1 binding protein]. 880 74

Some anaplastic large cell lymphomas (ALCLs) carry a specific chromosomal translocation, t(2;5)(p23;q35). Recently, we found a novel hyperphosphorylated 80-kDa protein tyrosine kinase, p80, in ALCLs with t(2;5). Subsequent cDNA cloning revealed p80 to be a fusion protein of two genes, the novel tyrosine kinase gene and the nucleophosmin gene, in accordance with the sequence of the NPM/ALK gene (Morris et al.). Meanwhile, the clinicopathologic features of p80-carrying ALCLs have remained unclear. Paraffin sections of 105 cases of ALCL were immunostained using anti-p80 antibody, and 30 of them were shown to express p80. Clinicopathological comparison between p80-positive and -negative ALCLs revealed that p80-positive cases occurred in a far younger patient age group and the patients showed a far better 5-year survival rate. These data showed that p80-positive ALCL is a distinct entity both clinically and pathogenetically, and should be differentiated from p80-negative ALCL.
Leukemia 1997 Apr
PMID:Anaplastic large cell lymphomas expressing the novel chimeric protein p80NPM/ALK: a distinct clinicopathologic entity. 920 50

Interferon regulatory factor-1 (IRF-1) acts as a transcriptional activator in the interferon system and as a tumor suppressor. The loss of functional IRF-1 has been observed in a significant number of patients with myelodysplastic syndrome (MDS) and leukemia, suggesting a potentially critical role of IRF-1 in human oncostasis. Here we report an alternative mechanism by which IRF-1 may be inactivated. We purified an IRF-1 association molecule which was revealed to be identical to a nuclear factor nucleophosmin (NPM)/B23/numatrin. Functional analysis showed that NPM inhibited the DNA-binding and transcriptional activity of IRF-1. Moreover, NPM was overexpressed in several clinical leukemia samples and human-derived leukemia cell lines. Finally, overexpression of NPM in NIH3T3 cells resulted in malignant transformation. These results suggest the possible involvement of NPM in inactivating IRF-1-dependent anti-oncogenic surveillance in human cancer development.
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PMID:Identification and characterization of nucleophosmin/B23/numatrin which binds the anti-oncogenic transcription factor IRF-1 and manifests oncogenic activity. 931 94

The myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein expressed specifically in developing cells of the human myelomonocytic lineage, including the end-stage monocytes/macrophages and granulocytes. Nuclear localization, lineage- and stage-specific expression, association with chromatin, and regulation by interferon alpha indicate that this protein is involved in regulating gene expression uniquely associated with the differentiation process and/or function of the monocyte/macrophage. MNDA does not bind specific DNA sequences, but rather a set of nuclear proteins that includes nucleolin (C23). Both in vitro binding assays and co-immunoprecipitation were used to demonstrate that MNDA also binds protein B23 (nucleophosmin/NPM). Three reciprocal chromosome translocations found in certain cases of leukemia/lymphoma involve fusions with the NPM/B23 gene, t(5;17) NPM-RARalpha, t(2;5) NPM-ALK, and the t(3;5) NPM-MLF1. In the current study, MNDA was not able to bind the NPM-ALK chimera originating from the t(2;5) and containing residues 1-117 of NPM. However, MNDA did bind the NPM-MLF1 product of the t(3;5) that contains the N-terminal 175 residues of NPM. The additional 58 amino acids (amino acids 117-175) of the NPM sequence that are contained in the product of the NPM-MLF1 fusion gene relative to the product of the NPM-ALK fusion appear responsible for MNDA binding. This additional NPM sequence contains a nuclear localization signal and clusters of acidic residues believed to bind nuclear localization signals of other proteins. Whereas NPM and nucleolin are primarily localized within the nucleolus, MNDA is distributed throughout the nucleus including the nucleolus, suggesting that additional interactions define overall MNDA localization.
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PMID:MNDA binds NPM/B23 and the NPM-MLF1 chimera generated by the t(3;5) associated with myelodysplastic syndrome and acute myeloid leukemia. 932 47

The nucleophosmin (NPM) gene is involved in two recurrent translocations in hematological malignancies: t(2;5) (p23;q35) in anaplastic large cell lymphoma (ALCL) and t(3;5)(q25.1;q34-35) in myelodysplasia and acute non-lymphocytic leukemia (ANLL). Using eight YACs encompassing the 5q34-q35 region, we could easily detect these two translocations. In both types of translocation, probable unexpected deletions were also discovered downstream of the breakpoint at 5q35.
Leukemia 1998 Jul
PMID:Non-Hodgkin's lymphomas and myeloid disorders: deletions associated with t(2;5) and t(3;5) detected by FISH. 966 4


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