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

A highly malignant human T-cell leukemia was identified by cell surface analysis as a member of the T-cell receptor (TCR) gamma delta lineage. Cytogenetic and molecular analysis showed a novel t(8;14)(q24;q11) rearrangement involving the J delta 1 gene segment on chromosome 14 and the distal end of chromosome 8 near the c-myc proto-oncogene locus. The gamma delta TCR of the leukemia blasts was functionally intact and could be activated to generate intracellular calcium flux and to target Fc receptor-mediated redirected tumor cell lysis. In addition, non-major histocompatibility complex restricted lysis of a limited target cell panel was shown by fresh leukemic blasts and by the in vitro-maintained leukemia cells that was comparable to known T-cell lines with natural killer-like activity. These data suggest that the T-cell leukemia potentially had in vivo functional cytolytic activity. However, whether this activity did contribute to the patient's clinical condition could not be determined.
 ...
PMID:A gamma delta+ T-cell leukemia bearing a novel t(8;14)(q24;q11) translocation demonstrates spontaneous in vitro natural killer-like activity. 153 37

Antibody-mediated ligation of the CD3/T cell antigen receptor (TcR) activates phospholipase C (PLC) via a tyrosine kinase signaling pathway that requires expression of the transmembrane tyrosine phosphatase CD45. In normal T cells, CD3-mediated PLC activation is significantly augmented by co-ligation of CD3 with the CD4 co-receptor; however, unlike CD3-associated tyrosine kinases, antibody-induced activation of the CD4-associated tyrosine kinase p56lck does not require CD45 expression. To explore the role of CD45 in the CD3 and CD4 activation pathways further, we examined the effect of CD3/CD4 cross-linking on tyrosine phosphorylation and activation of phospholipase C in CD45- mutant cells of the T cell leukemia line HPB.ALL. In accord with previous observations, anti-CD3 stimulation of the CD45-deficient cells failed to activate tyrosine kinases, or PLC as measured by mobilization of intracellular calcium. However, we show here that ligation of CD3 with CD4 leads to tyrosine phosphorylation of PLC gamma 1 and elevation in the intracellular free Ca2+ concentration in CD45- cells that is in excess of that seen in CD45+ cells. Since CD4 stimulation alone did not activate PLC, a component of the CD3 signaling pathway must be independent of CD45. Anti-CD4-induced tyrosine phosphorylation and activation of CD4-associated lck was also enhanced in CD45- cells, suggesting that increased lck activation compensates for the defect in CD3/TcR signaling, such that interaction of the CD3 signaling pathway with the CD4-associated pathway activates PLC even in the absence of CD45. The data demonstrate that the requirement for CD45 in coupling CD3/TcR to the PI-PLC activation cascade is not absolute, but rather substantiates a role for CD45 in modifying molecular interactions that control T cell activation.
 ...
PMID:Interaction of CD4:lck with the T cell receptor/CD3 complex induces early signaling events in the absence of CD45 tyrosine phosphatase. 153 48

Recent studies in rat basophilic leukemia cells (RBL-2H3) have shown that two pharmacological agents, ionomycin and thapsigargin, induce leukotriene C4 production and translocation of 5-lipoxygenase from cytosol to membrane, primarily by causing an influx of extracellular calcium. In the present study, we investigate the induction of these events by receptor activation. Cross-linking of high-affinity IgE receptors (Fc epsilon RI) by antigen in RBL-2H3 cells leads to leukotriene C4 production and membrane translocation of 5-lipoxygenase. As in the ionomycin-stimulated cells, leukotriene C4 production in antigen-stimulated cells is calcium-dependent since the amount of leukotriene C4 produced correlates quantitatively with the increase in intracellular free calcium concentration ([Ca2+]i). However, the increase in [Ca2+]i required for equivalent leukotriene C4 production by antigen is not as high as it is using ionomycin. In addition, no threshold [Ca2+]i level is required for leukotriene production by antigen, which is in contrast to the ionomycin stimulation that a [Ca2+]i level of 300-400 nM is required. Furthermore, antigen causes an additive increase in leukotriene C4 production in cells stimulated by the ionomycin. These results suggest that another as yet unidentified intracellular pathway acts in conjunction with Ca2+ for leukotriene synthesis in antigen-stimulated cells. Antigen stimulation causes 20-30% of the total cell 5-lipoxygenase to associate with membranes (compared with 10% in unstimulated cells) as demonstrated by enzyme activity assay and by Western Blot using antibodies to 5-lipoxygenase.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Stimulation of leukotriene production and membrane translocation of 5-lipoxygenase by cross-linking of the IgE receptors in RBL-2H3 cells. 153 55

Mast cells respond to clustering of the type I Fc epsilon receptor (Fc epsilon RI) on their membranes by mediator secretion. Recently, a marked enhancement of tyrosine phosphorylation on several proteins has been observed as a result of antigen-induced Fc epsilon RI aggregation on these cells. We report here that the phosphatidyl inositide specific phospholipase C gamma 1 (PLC gamma 1) is one of the prime proteins that undergoes tyrosine phosphorylation as a result of this stimulus. This was determined by immunoprecipitation of phosphotyrosine containing proteins from detergent lysates of rat mucosal mast cells (rat basophilic leukemia cells, subline 2H3; RBL-2H3) and Western blotting analysis of the separated components. A fast appearance of phosphorylated tyrosine residues on PLC gamma 1 was observed, reaching its maximal intensity at approximately 1-3 min after stimulation and declined afterwards to basal levels. Moreover, the phosphorylation depended on maintaining the aggregated Fc epsilon RI as did other cellular responses (e.g. phosphatidyl inositides hydrolysis and secretion). The time course of both Fc epsilon RI induced phospholipase C gamma 1 activation, as monitored by the formation of inositol phosphates, and of the secretory response of the cells followed that of the PLC gamma 1 phosphorylation. Furthermore, the tyrphostin AG490, a protein tyrosine kinase inhibitor, caused similar inhibition of the Fc epsilon RI-induced PLC gamma 1 phosphorylation, inositol phosphates formation, and mediator secretion. Significantly, no tyrosine phosphorylation of PLC gamma 1 was induced by the Ca2+ ionophore, ionomycin, even at doses that cause optimal secretory response.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Tyrosine phosphorylation of phospholipase C gamma 1 couples the Fc epsilon receptor mediated signal to mast cells secretion. 153 54

In RBL-2H3 rat basophilic leukemia cells, Ca2+ influx and secretion are activated by antigens that crosslink IgE-receptor complexes and by the Ca2+ ionophore, ionomycin. Here we report that antigen-stimulated Ca2+ influx and secretion are impaired and ionomycin-induced responses are strongly inhibited following the removal of HCO3- from the medium. These results raised the possibility that HCO3(-)-dependent pH regulation mechanisms play a role in the cascade of events leading to mast cell activation. To test this hypothesis, intracellular pH (pHi) was measured by ratio imaging microscopy in individual RBL-2H3 cells labeled with 2',7'-bis-(2-carboxyethyl)-5-(6) carboxyfluorescein (BCECF). In unstimulated cells, it was found that basal pHi in the presence of HCO3- is 7.26, significantly greater than pHi in its absence, 7.09 (P less than 10(-6]. These results, as well as evidence that pHi increases rapidly when HCO3- is added to cells initially incubated in HCO3(-)-free medium, indicate that unstimulated cells use a HCO3(-)-dependent mechanism to maintain cytoplasmic pH. Further analyses comparing unstimulated with stimulated cells showed that antigen causes a small transient acidification in medium containing HCO3- and a larger sustained acidification in HCO3(-)-depleted medium. Ionomycin is a more potent acidifying agent, stimulating a sustained acidification in complete medium and causing further acidification in HCO3(-)-free medium. These results support the hypothesis that the inhibition of antigen- and ionomycin-induced 45Ca2+ influx and secretion in cells incubated in HCO3(-)-free medium is at least partially due to the inactivation of HCO3(-)-dependent mechanisms required to maintain pH in unstimulated cells and to permit pH recovery from stimulus-induced acidification.
 ...
PMID:Importance of bicarbonate ion for intracellular pH regulation in antigen- and ionomycin-stimulated RBL-2H3 mast cells. 154 61

We have identified and partially purified a novel cytolytic factor isolated from enriched plasma membranes prepared from highly purified lymphokine-activated killer cells (adherent-LAK. A-LAK cells) and a large granular lymphocytic NK cell leukemia, CRNK-16. The enriched plasma membranes were shown to be physically devoid of lytic granules and contained no detectable pore-forming protein (PFP, perforin) activity. The plasma membrane-associated cytolytic factor (designated M-CTX) was solubilized in biologically active form and was highly lytic to a large panel of target cells in 2- to 4-hr 51Cr release assays. Characteristics of the M-CTX include: (1) it is plasma membrane- not granule-associated: (2) it is not hemolytic and functions in the absence of Ca2+: (3) nucleated target cells are lysed in 2 to 4 hr at 37 degrees C but not at 4 degrees C: (4) it induces apoptotic cell death with nuclear DNA fragmentation and massive membrane blebbing: (5) it is isolated from the plasma membranes of cultured A-LAK cells, a lytically active LGL leukemia (CRNK-16), and fresh spleen cells but not from thymocytes or L929 fibroblasts: and (6) the lytic activity of the partially purified toxin is inactivated by trypsin, serum, and heat, but is not blocked by antibodies that inactivate TNF-alpha, LT or IFN-gamma. Taken collectively, these data suggest that M-CTX may represent a heretofore undescribed membrane-associated toxin possibly involved in contact-mediated cell killing.
 ...
PMID:Identification and partial characterization of a novel plasma membrane-associated lytic factor isolated from highly purified adherent lymphokine-activated killer cells. 155 54

1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3)-induced differentiation of HL-60 leukemia cells is accompanied by a number of cellular changes including regulation of oncogene expression and induction of terminal differentiation. We investigated the mechanism by which 1,25-(OH)2D3 induces these changes. We detected 10 nuclear phosphoproteins, designated p66, p45, p36, p33, p32, p27, p22, p19, p18 and p17, that show alterations in phosphorylation within 6-40 h of 1,25-(OH)2D3 treatment. When phosphorylation reactions were performed with isolated nuclei (in vitro), three of these proteins were phosphorylated in a calcium and phospholipid dependent manner: p66, p36, and p19 P66 was phosphorylated in response to 1,25-(OH)2D3 and purified in a manner similar to that used for nuclear lamins. Western blot analysis of 2-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) gels confirmed its identity as lamin B. Phosphorylation of p17 and p18 decreased following 1,25-(OH)2D3 treatment. We separated p17 and p18 by SDS-PAGE and obtained N-terminal amino acid sequence to identify these phosphorproteins as histones H2b and H3, respectively. P19 and p22 were both DNA-cellulose binding proteins whose phosphorylation was altered by 1,25-(OH)2D3 treatment. Increased phosphorylation of p27 was detected using 2-dimensional SDS-PAGE. Phosphorylation of nuclear proteins in the intact cell (in vivo), revealed increases in p66, p45, p36, and p33 phosphorylation and a decrease in p17 phosphorylation following 1,25-(OH)2D3 treatment. We detected an increase in phosphorylation of p32, which was extracted with salt from nuclei and migrated on SDS-PAGE similar to histone H1. Thus, we have identified 1,25-(OH)2D3-sensitive nuclear phosphoproteins, including lamin B and several histones. We have also detected and characterized several less abundant nuclear DNA binding phosphoproteins whose phosphorylation was affected by 1,25-(OH)2D3.
 ...
PMID:Identification of lamin B and histones as 1,25-dihydroxyvitamin D3-regulated nuclear phosphoproteins in HL-60 cells. 155 89

The P2T purinergic receptor for ADP has previously been found only in platelets. We investigated the effect of ADP on the concentration of intracellular free calcium ([Ca++]i) in fura-2-loaded K562 leukemia cells, a cell line with the potential for megakaryocytic differentiation. ADP causes a rapid and transient increase in [Ca++]i, which peaks within 5 to 10 sec. The EC50 for this response is 0.4 microM. A major portion of the increased calcium is due to mobilization of intracellular stores because the response to ADP is only partially reduced in the absence of extracellular calcium. Exposure to ADP desensitizes K562 cells to additional administrations of this nucleotide. Pretreatment of K562 cells with the protein kinase C activator phorbol 12-myristate 13-acetate completely blocks the response to ADP. This effect of phorbol 12-myristate 13-acetate is prevented by the protein kinase C inhibitor staurosporine, but staurosporine does not affect the progression of desensitization after repeated ADP exposures. ATP does not increase [Ca++]i in K562 cells, but antagonizes the response to ADP. We propose that the P2T receptor for ADP in K562 cells is an early marker for megakaryocytic differentiation. Furthermore, this immortalized nucleated cell line may be a useful model to decipher the signal transduction pathways involved in the ADP response.
 ...
PMID:K562 leukemia cells express P2T (adenosine diphosphate) purinergic receptors. 157 75

We studied the activation signals of LGL, from LDGL patients, following incubation with susceptible K562 target cells. The findings showed that LGL lysis is independent of [Ca2+]i rise and cytolytic granule exocytosis, and most likely involves alternative, as yet unidentified, mechanisms.
Leukemia 1992
PMID:Interaction of large granular lymphocytes with susceptible target does not induce second messenger and cytolytic granule exocytosis. 160 35

Basophils located in tissues are called mast cells and are found in connective tissue. Many different compounds are secreted from basophil granules upon appropriate stimulation. Products such as heparin, histamine, serotonin (5-hydroxytryptamine, 5-HT), and membrane-derived materials which give rise to arachidonic acid metabolites, such as prostaglandins and leukotrienes, are some of the more important compounds released by mast cells. These compounds, when released after stimulation with a variety of molecules, such as IgE, specific antigen anaphylotoxin, as well as the compound 48/80 (C48/80) or calcium ionophore A23187, cause contraction of endothelial cells and mediate atopic or anaphylactic hypersensitivity. In this report, we study the generation of some arachidonic acid products, namely leukotrienes C4, D4, E4, and B4 and the prostaglandins D2 and E2 by rat peritoneal mast cells (RPMC), using calcium ionophore A23187 as a degranulating agonist. We have also studied the new lipoxygenase products, lipoxins A4 and B4, on RPMC secretion using C48/80 as a secretagogue. A rat basophilic leukemia cell line (RBL) was also used to compare results with RPMC. In this paper we have demonstrated that RPMC stimulated with A23187 release LTC4, LTD4, LTE4 and LTB4 and also PGD2 but not PGE2. These results were also confirmed when RBLs were used. In addition, we have shown that mast cells pretreated with LTC4, LTD4, LTE4 or 15-HETE do not modify the release of [3H]5HT exerted by C48/80 (0.5 microgram/ml) or A23187 (5 micrograms/ml). When LXA4 or B4 was used, mast cells were inhibited slightly (not statistically significant) from degranulating after the secretagogue treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Role of lipoxins A4 and B4 in the generation of arachidonic acid metabolites by rat mast cells and their effect on [3H]serotonin release. 161 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>