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)

The metabolism of 1-[3H]alkyl-2-acetyl-sn-glycero-3-phosphocholine (1-[3H]alkyl-2-acetyl-GPC; platelet-activating factor; PAF) was investigated in purified human peripheral blood T-lymphocytes and a human leukemia cell line of T-cell origin (MOLT-4). The major metabolic products of T-lymphocyte PAF metabolism are 1-alkyl-2-acyl-GPC, 1-alkyl-2-lyso-GPC and neutral lipid. The pattern of PAF metabolism in peripheral blood T-lymphocytes and MOLT-4 lymphoblasts was similar, although MOLT-4 lymphoblasts transformed PAF to 1-alkyl-2-acyl-GPC faster than peripheral blood T-lymphocytes (67% vs. 21% of added label after 64 min at 37 degrees C, respectively). Pre-exposure of MOLT-4 lymphoblasts to 1 mM of the serine hydrolase inhibitor phenylmethylsulfonyl fluoride resulted in an inhibition of PAF metabolism. Our results indicate that intact T-lymphocytes actively metabolize this biologically active phospholipid by the deacetylation-transacylation pathway.
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PMID:The metabolism of platelet-activating factor in human T-lymphocytes. 230 20

In rat basophilic leukemia cells (2 H3-RBL) stimulated with the calcium ionophore A23187, a rapid build-up of PAF-acether was observed within 5 minutes. Thereafter, a slow and complete catabolism was observed within the next 55 minutes. Accumulation of PAF-acether required calcium in the medium and was increased in the presence of acetyl-CoA. Phenyl methyl sulfonyl fluoride, a serine hydrolase inhibitor active on 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine acetyl hydrolase also produced an increased accumulation of PAF-acether in ionophore-stimulated cells. Quinacrine, a non specific inhibitor of phospholipase A2 impaired PAF-acether formation in a dose-dependent manner. The time-course of PAF-acether formation was compared with the ionophore-induced release of arachidonic acid from these cells.
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PMID:Platelet-activating factor (PAF-acether) formation in rat basophilic leukemia cells stimulated by ionophore A23187. 312 May 19

The platelet activating factor receptor (hPAFR) is a GTP binding protein linked receptor of the rhodopsin family. The hPAFR gene maps to chromosome 1 and is characterized by the absence of introns in its coding region. Because PAF demonstrates unique properties as a growth factor in human B lymphoblastoid cell lines, we developed an RT-PCR in order to detect the presence of hPAFR mRNA. We examined the presence of the hPAFR in a series of B lymphoblastoid cell lines, as well as on fresh human B cells and the T-leukemia cell line Jurkat. All cells of B lineage expressed hPAFR mRNA, including a B cell line not previously shown to express functional hPAFR. In contrast, the T-leukemia cell line Jurkat expressed very low levels of hPAFR mRNA. We discuss the methodology and its validation in developing an RT-PCR for intronless genes such as the hPAFR.
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PMID:Detection of the human platelet-activating factor receptor mRNA in human B lymphocytes by polymerase chain reaction on reverse transcripts (RT-PCR) 806 Mar 16

Recently, a human eosinophilic leukemia cell line, EoL was established from an eosinophilic leukemia patient. EoL-1 cells have the cytohistologic features of myeloblasts under normal culture conditions, and they can be induced to differentiate into eosinophilic granule-containing cells but not into other lineage cells under several culture conditions and are therefore considered to be committed precursors of eosinophils. Furthermore, EoL-1 cells can also be induced to differentiate functionally to show PAF-induced Ca2+ influx and actin polymerization. On the other hand, EoL-3 cells show constitutive expression of Fc epsilon RII, Fc gamma RII, LFA-1 and ICAM-1 on their cell surface. The EoL cells may provide new information on some aspects of the signal transduction mechanisms involved in the proliferation, differentiation and activation of eosinophils.
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PMID:[Review: recent studies on a human eosinophilic leukemia cell line, EoL as an experimental model of eosinophils]. 809 79

The inhibitory effects of azelastine hydrochloride on PAF-induced and fMLP-induced Ca2+ influx, actin polymerization and calcium ionophore A23187-induced and aggregated IgG-induced release of eosinophil cationic protein (ECP) of an eosinophilic leukaemia cell line, EoL-1, were examined. EoL-1 cells cultured with 0.2 mM dibutyryladenosine-cyclic monophosphate for 48 hours showed an increase in intracellular free Ca2+ concentration ([Ca2+]i) and actin polymerization when stimulated by PAF and fMLP. Azelastine hydrochloride inhibited PAF-induced and fMLP-induced Ca2+ influx ([Ca2+]i) in a dose-dependent manner with an IC50 of 1 x 10(-8) M and 1 x 10(-7) M, respectively. It also inhibited PAF-induced and fMLP-induced actin polymerization in a dose-dependent manner up to 40% and 30%, respectively. EoL-1 cells were differentiated to contain ECP in their eosinophilic granules when cultured for 9 days with supernatants of a human adult T cell leukaemia cell line, HIL-3 (HIL-3 sup). Calcium ionophore A23187 and aggregated IgG induced the secretion of ECP by EoL-1 cells. Azelastine hydrochloride inhibited the secretion of ECP in a dose-dependent manner. These inhibitory effects were seen even at therapeutic concentrations of 10(-8) M to 10(-9) M. These results indicate that the therapeutic effects of azelastine hydrochloride as an anti-allergic agent may include inhibition of the accumulation of eosinophils into the locus of allergic inflammation and of the release of cytotoxic granules from eosinophils.
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PMID:Inhibitory effects of azelastine hydrochloride on Ca2+ influx, actin polymerization and release of eosinophil cationic protein of an eosinophilic leukaemia cell line EoL-1. 822 44

Human eosinophilic leukemia (Eol-1) cells were examined for their ability to generate platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) (PAF) and the effect of supplementation of docosa-hexaenoic acid (C22:6n-3) (DHA) on the PAF synthesis was explored in relation to the fatty acid composition of phospholipids and the liberation of arachidonic acid (C20:4n-6 AA). Although undifferentiated cells did not produce PAF, the exposure of IFN-gamma differentiated Eol-1 to generate PAF in response to the Ca-ionophore. In addition, the IFN-gamma-treated cells acquired the ability to release free fatty acids, approximately 55% of which was found to be AA. When DHA was supplemented into the culture of Eol-1 for 24 h, PAF production decreased by 40 to 50% at concentrations of 3 to 10 microM. On the other hand, supplementation of 10 microM eicosapentaenoic acid (C20:5n-3) did not significantly decrease PAF production. With the supplementation of 10 microM DHA, DHA levels in phospholipid subclasses, including alkylacylglycerophosphocholine, were greatly increased with concurrent decreases in other unsaturated fatty acids. In these cells, the liberation of AA in response to an ionophore was decreased by 55%. Even when DHA was enriched in phospholipids, DHA release in response to ionophore stimulation was almost negligible, indicating that the DHA moiety of phospholipids is not susceptible to the action of phospholipase A2. Furthermore, DHA supplementation appeared to attenuate phospholipase A2 reaction by some unknown mechanism because the decrease in AA release was much more than that for the AA level in phospholipids. Acetyl-CoA:1-alkylGPC acetyltransferase activity of stimulated cell lysate was also reduced by DHA supplementation but the reduction was much less when compared with that of PAF synthesis or AA release. These results implicated that enrichment of DHA attenuates enzymic reactions for PAF synthesis, mainly the initial reaction catalyzed by AA-specific phospholipase, and thereby reduces PAF synthesis in Eol-1.
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PMID:Effect of docosahexaenoic acid on the generation of platelet-activating factor by eosinophilic leukemia cells, Eol-1. 846 86

The cytolytic activity of human plasma free platelets treated with various stimulators (Ca-ionophore, PAF (platelet activating factor), PHA, and ricin) has been studied on human erythroid leukemia cell line (K562). The 14 kDa and 28 kDa platelet cytotoxic factors (PCF) have been purified from the supernatant obtained from platelets stimulated by 10(-7) M Ca-ionophore. The PCF-14 N-terminal sequence ((1)YAPQXQFGP(9)-) appeared to be homologous to the region 241-249 residues of the human C1s complement component. The PCF-28 N-terminal sequence (DVGLT-) did not display any homology to known human proteins. The PCF-14 and the PCF-28 have been detected both in the supernatants of platelets treated with various stimulators (10(-7) M Ca-ionophore A23187, or 10(-8) M PAF, or 10(-9) M PHA, or 10(-13) M ricin) and in the extracts of disrupted platelets treated by these stimulators. All of these stimulators enhanced the production of thromboxane A(2) by platelets, as evidenced from the accumulation of thromboxane B(2), a spontaneous hydrolysis product of thromboxane A(2). These results indicate that platelet cytotoxicity to the K562 cells and the release of PCF-14 and PCF-28 might be mediated by the stimulation of thromboxane A(2) synthesis, when platelets have been activated through the cycloxygenase pathway.
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PMID:Stimulation of Human Platelet Cytotoxicity by Various Activators in the Absence of Antibodies: Release of Thromboxane A2 and Soluble Cytotoxic Factors. Purification and Partial Characterisation of 14 and 28 kDa Cytotoxic Proteins. 1268 2

PAF-receptor antagonists WEB-2086 and WEB-2170 (WEBs) have been previously shown to induce differentiation in murine and human leukemia cells. The present study describes the apoptotic-differentiative effect of WEBs in all-trans-retinoic acid (ATRA)-sensitive (NB4) and -resistant (NB4-007-6 and NB4-MR4) acute promyelocytic leukemia (APL) cell lines as well as blasts from patients with t(15;17) APL. NB4 cells exposed to 0.5-1 mM WEBs underwent striking growth arrest and massive apoptosis without appreciable differentiation; IC50 values after 3-day treatment of NB4 were 0.4 and 0.25 mM for WEB-2086 and WEB-2170, respectively. WEBs induced apoptosis also in the two ATRA-resistant NB4-007-6 and NB4-MR4 cell lines and in blasts from patients with t(15;17) APL. Moreover, subapoptotic WEBs acted synergistically with low-dose (0.025-0.05 microM) ATRA; this allowed to increase ATRA differentiation potential up to 40-fold and to improve both number and intensity of NBT-positive NB4 cells at definitely higher levels than with 1 muM ATRA alone. The powerful antiproliferative-apoptotic activities of WEBs in vitro on ATRA-sensitive, ATRA-resistant APL cells and blasts from patients with APL as well as drug capabilities to enhance ATRA differentiation potential suggested that these agents also due to their recognized tolerability in vivo might improve, alone or in combination, clinical treatment of APL.
Leukemia 2005 Mar
PMID:WEB-2086 and WEB-2170 trigger apoptosis in both ATRA-sensitive and -resistant promyelocytic leukemia cells and greatly enhance ATRA differentiation potential. 1567 64

Platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycerolphosphocholine; PAF) induces leukocyte accumulation and activation at sites of inflammation via the activation of a specific cell surface receptor (PAFR). PAFR couples to both pertussis toxin-sensitive and pertussis toxin-insensitive G proteins to activate leukocytes. To define the role(s) of G(i) and G(q) in PAF-induced leukocyte responses, two G-protein-linked receptors were generated by fusing G alpha(i3) (PAFR-G alpha(i3)) or G alpha(q) (PAFR-G alpha(q)) at the C terminus of PAFR. Rat basophilic leukemia cell line (RBL-2H3) stably expressing wild-type PAFR, PAFR-G alpha(i3), or PAFR-G alpha(q) was generated and characterized. All receptor variants bound PAF with similar affinities to mediate G-protein activation, intracellular Ca2+ mobilization, phosphoinositide (PI) hydrolysis, and secretion of beta-hexosaminidase. PAFR-G alpha(i3) and PAFR-G alpha(q) mediated greater GTPase activity in isolated membranes than PAFR but lower PI hydrolysis and secretion in whole cells. PAFR and PAFR-G alpha(i3), but not PAFR-G alpha(q), mediated chemotaxis to PAF. All three receptors underwent phosphorylation and desensitization upon exposure to PAF but only PAFR translocated beta arrestin to the cell membrane and internalized. In RBL-2H3 cells coexpressing the PAFRs along with CXCR1, IL-8 (CXCL8) cross-desensitized Ca2+ mobilization to PAF by all the receptors but only PAFR-G alpha(i3) activation cross-inhibited the response of CXCR1 to CXCL8. Altogether, the data indicate that G(i) exclusively mediates chemotactic and cross-regulatory signals of the PAFR, but both G(i) and G(q) activate PI hydrolysis and exocytosis by this receptor. Because chemotaxis and cross-desensitization are exclusively mediated by G(i), the data suggest that differential activation of both G(i) and G(q) by PAFR likely mediate specific as well as redundant signaling pathways.
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PMID:Activation and regulation of platelet-activating factor receptor: role of G(i) and G(q) in receptor-mediated chemotactic, cytotoxic, and cross-regulatory signals. 1692 Sep 64

MLL1 fusions are among the most potent oncogenic drivers of leukemia development. In recent articles published in Molecular Cell and in Cancer Cell, researchers find that MLL1 fusions are reliant on a physical interaction with the PAF transcription elongation complex for their recruitment to chromatin and, consequently, leukemic transformation.
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PMID:PAF is in the cabal of MLL1-interacting proteins that promote leukemia. 2054 97


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