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)

Activation of resting human peripheral blood T lymphocytes by the lectin phytohemagglutinin results in an increase in methionine adenosyltransferase (MAT) activity, accompanied by an increase in the amount of the alpha/alpha' catalytic subunits of the enzyme. In contrast, the amount of the noncatalytic beta subunit remains constant throughout the course of the response. Using both polyclonal antibodies to the holoenzyme and monoclonal antibodies to the alpha/alpha' subunits, we detected a cross-reactive 68-kDa protein, which we refer to as lambda. This protein is present in high abundance in resting T cells but decreases upon cell stimulation, as both MAT activity and the amount of the catalytic alpha/alpha' subunits increase. The decrease in lambda and increase in alpha/alpha' occurs after interleukin-2 production and before DNA synthesis. lambda virtually disappears when the cells are actively dividing. Several continuous T cell lines (HPB-ALL, MOLT-4, and Jurkat) as well as a freshly isolated T cell leukemia (ALL-2) had no detectable lambda. The Km for L-methionine for enzyme from resting peripheral blood mononuclear cells was 19-23 microM, which is 3-8-fold higher than purified MAT from fresh leukemic cells or enzyme from Jurkat cells, both of which have a Km of 3.5-3.8 microM. Kinetic analysis of enzyme activity from activated peripheral blood mononuclear cells suggested the presence of two forms of enzyme catalyzing the synthesis of AdoMet. After separation of lambda from the alpha and beta subunits by hydrophobic chromatography, it was determined that lambda has MAT activity but that it is significantly less active than the form containing the alpha subunit. It therefore appears that in resting T cells MAT is sequestered as a less active form. We hypothesize that lambda is a precursor to the catalytic subunits of human lymphocyte MAT and propose that the transition from lambda to alpha/alpha' may be important in the response of T cells to mitogenic signals.
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PMID:Changes in the relative amount of subunits of methionine adenosyltransferase in human lymphocytes upon stimulation with a polyclonal T cell mitogen. 158 46

We have recently reported that methionine adenosyltransferase (MAT) in resting human peripheral blood T-cells is primarily present in the form of a precursor which we named lambda. This protein decreases upon cell stimulation, as both MAT activity and the amount of the catalytic alpha/alpha' subunits of the enzyme increase. When resting cells are activated by phytohemagglutinin, the decrease in lambda and increase in alpha/alpha' occurs after interleukin 2 (IL-2) production and before DNA synthesis. The human T-leukemia cell line, Jurkat, is unique in its ability to produce IL-2 in response to exogenous stimuli such as T-cell mitogens and therefore provides a convenient model for studying biochemical reactions involved in T-cell activation. In this study the regulation of MAT activity and S-adenosylmethionine (AdoMet) in resting and activated Jurkat cells was investigated. Here we report that MAT activity in unstimulated Jurkat cells is about 10- and 3-fold higher than the activity in resting and activated peripheral blood mononuclear cells, respectively. Activation of Jurkat cells with phytohemagglutinin resulted in increased IL-2-production, but not an increase in MAT activity. Identical results were obtained using freshly isolated cells from acute lymphoblastic leukemia patients. AdoMet utilization and pool size were approximately 3- and 10-fold higher, respectively, in Jurkat cells compared to peripheral blood mononuclear cells, and both parameters were unaffected by phytohemagglutinin stimulation. Jurkat MAT was determined to be structurally indistinguishable from enzyme from T- or B-leukemia cells but was different from resting, normal T-cells in that it lacked the lambda form. Furthermore, unlike MAT in resting T-cells, the relative amounts of the alpha, alpha', and beta subunits of the enzyme did not change throughout the course of IL-2 induction. We conclude that AdoMet metabolism and MAT activity in Jurkat cells are constitutively high and that induction of IL-2 synthesis in these cells is independent of changes in AdoMet synthesis or turnover. The lack of the lambda form and the difference in MAT regulation between leukemic T-cells and peripheral blood mononuclear cells may be exploited in the design of specific chemotherapeutic agents.
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PMID:Induction of interleukin 2 production but not methionine adenosyltransferase activity or S-adenosylmethionine turnover in Jurkat T-cells. 159 94

Myelo-cytotoxicity of extended nitrous oxide (N2O) inhalation was described almost forty years ago and then incidentally applied already with temporary success for suppressing leukemia. In 1948 the accompanying megaloblastic maturation arrest was explained by inactivation of the methylcobalamin coenzyme and subsequent folate deficiency. We studied the anti-leukemic effect of N2O on a transplantable acute leukemia in B(rown) N(orway) rats. Progression of this B,N,M(yelocytic)L(eukemia) was measured as spleen and liver weights, and leukemic blood cell counts. The deoxyuridine (dU)-suppression test provided in vitro indication of the functional folate activity of leukemic cells. Breathing of N2O-oxygen considerably reduced but did not eradicate, BNML-proliferation. Addition of anti-metabolites, interfering with some enzyme in the folate metabolism beyond the methylcobalamin co-enzyme dependent methionine synthase step, acted at least synergistically. The anti-leukemic effect of cycloleucine, which reduces S-adenosyl-methionine synthesis by inactivation of methionine adenosyltransferase, was moderate but became much stronger with N2O inhalation. Methotrexate, a potent anti-leukemic agent by inhibiting tetrahydrofolate (THF) generation through inactivation of di-HF reductase, became highly anti-BNML, even in low dosage when combined with or preceded by N2O. 5-Fluorouracil, which inhibits methylene-THF dependent thymidilate synthase, itself was surprisingly anti-BNML, but also became much more potent with previous or concomitant N2O exposure. Preliminary dU-suppression test results with human acute leukemia cells, exposed to N2O and/or folate antagonists in vitro, correlated well with the in vivo BNML-experiments. Combining the anticobalamin activity of N2O with an anti-folate therefore seems to be a promising chemotherapeutic approach.
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PMID:Anti-leukemic potential of methyl-cobalamin inactivation by nitrous oxide. 218 35

The in vitro sensitivity of bone marrow cells from patients with leukaemia and from patients with non-malignant diseases to L-methionine removal by L-methioninase (L-methionine-alpha-deamino-gamma-mercaptomethane-lyase, EC 4.4.1.11) was determined using the incorporation of [methyl-3H]thymidine into acid-insoluble material as an index of survival. When compared with controls growing in medium containing 10 micrograms/ml of L-methionine, leukaemic cells showed a lower incorporation of [methyl-3H]thymidine after 24 h in the presence of 0.1 (normal 78 +/- 24%; leukaemic 26 +/- 18%, p less than 0.01) or 0.05 (normal 84 +/- 15%; leukaemic 50 +/- 21%, p less than 0.01) units of L-methioninase per ml. A similar differential sensitivity of leukaemic cells to L-methioninase was seen after 48 h of incubation. There was little effect on [methyl-3H]thymidine incorporation in the presence of boiled enzyme. Attempts to reverse L-methioninase toxicity with D-homocystine did not result in a differential effect on the normal cell population. The effects of L-methionine removal with L-methioninase were similar to those observed in L-methionine-depleted culture medium supplemented with 0.1 mM L-homocysteine. After 24 h in such depleted media leukaemic cells showed a lower incorporation of [methyl-3H]thymidine into acid-insoluble material (normal 88 +/- 17%; leukaemic 35 +/- 14%, p less than 0.01) and there was an elevation of the L-methionine-dependent enzymes: methionine adenosyltransferase, tRNA methyltransferase and S-adenosylmethionine decarboxylase. These results suggest the possibility of trying L-methioninase in the treatment of suitable leukaemias.
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PMID:Differential sensitivity of normal and leukaemic haemopoietic cells to methionine deprivation by L-methioninase. 685 69

We have characterized HIMeg-1, a subclone of the promegakaryoblastic cell line HIMeg, in terms of its capability of proliferation and differentiation when it is exposed to various agents. We observed that phorbol 12-myristate 13-acetate (PMA) arrested HIMeg-1 growth and induced expression of monocytic surface antigens CD11c and CD14, but not the megakaryocytic surface antigen CD14a. In addition, PMA treatment of HIMeg-1 led to rapid activation of mRNA expression of egr-1, a transcription factor involved in regulating differentiation of hematopoietic progenitor cells. On the other hand, treatment of HIMeg-1 with the activated peripheral blood lymphocyte-conditioned medium (PBL-CM) resulted in greatly enhanced incorporation of 3H-thymidine into newly synthesized DNA. This enhanced 3H-thymidine incorporation appears to be specific to HIMeg-1 since the same concentrations of PBL-CM had little effect on the growth of the megakaryoblastic leukemia cell line SAM-1. The PBL-CM-induced DNA synthesis in HIMeg-1 was associated with activation of CD41a and CD41b surface antigen expression and down-regulation of expression of the erythroid marker glycophorin A and the early myeloid surface antigen CD33. HIMeg-1 capable of responding differentially to PMA and PBL-CM by changing its growth rate as well as its differentiation patterns will provide an ideal model to study the underlying mechanism regulating lineage restriction of hematopoietic progenitor cells.
Leukemia 1995 Jul
PMID:HIMeg-1, a cell line derived from a CML patient, is capable of monocytic and megakaryocytic differentiation. 754 77

A congenic strain of mice with amyloidogenic apolipoprotein A-II (Apoa2c) on the genetic background of the amyloidosis-resistant SAM-R/1 strain was produced by 12 generations of backcrossing. Genome mapping using endogenous murine leukemia proviral markers was done in the congenic strain, termed R1.P1-Apoa2c. We confirmed that only a small region surrounding the apoA-II gene on chromosome 1 was transferred from the genome of the donor SAM-P/1 strain. The level and particle size of plasma high density lipoprotein were decreased in R1.P1-Apoa2c mice compared to those in the progenitor SAM-R/1 mice. The function of apoA-II can be studied using this strain of mice.
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PMID:Development of congenic strains of mice carrying amyloidogenic apolipoprotein A-II (Apoa2c). Apoa2c reduces the plasma level and the size of high density lipoprotein. 838 Oct 93

Cell surface-expressed proteoglycans mediate contacts to extracellular matrix (ECM). Human B lymphocytes produce a species of a proteochondroitin sulfate (CSPG) with an approximate molecular mass of 135-150 kDa. Using a monoclonal antibody (mAb) against B cell CSPG in flow cytometry we found that this CSPG is expressed on tumor cells of patients with CD19+ common acute lymphoblastic leukemia and on the corresponding cell lines Nalm-6, Reh and KM3. The CSPG is also present on hairy cell leukemia JOK-1 cells and weakly on the myeloma line U266. Concomitant with CSPG expression, Nalm-6 cells express the integrins alpha 5/beta 1 (CD49e/CD29) and alpha 6/beta 1 (CD49f/CD29), adhesion receptors for fibronectin and laminin, in contrast to the other two cell lines tested. Expression patterns of these adhesion receptors and CSPG were paralleled by strong adhesion of Nalm-6 to fibronectin and laminin. Adhesion of Nalm-6 to fibronectin was inhibited by the alpha 5-specific antibody SAM 1 by 80% whereas the alpha 6-specific antibody GoH3 reduced binding to laminin only by 20%. A possible involvement of surface-expressed CSPG in adhesion to ECM components was investigated by 24 h incubation of Nalm-6 cells with p-nitrophenyl-beta-D-xyloside, an inhibitor of proteoglycan glycosylation. By this treatment, both adhesion of Nalm-6 to laminin and expression of CSPG were reduced by 40-50%. Furthermore, addition of chondroitin-6-sulfate, a structural element of Nalm-6 CSPG, reduced adhesion of Nalm-6 to laminin by 60%. Chondroitin-4-sulfate, heparin and heparan sulfate did not effectively inhibit the adhesion process. These observations suggest that surface-expressed CSPG may be involved in binding of Nalm-6 cells to laminin and that the specific sulfation pattern of chondroitin-6-sulfate may be essential in this regard.
Leukemia 1996 Jun
PMID:Characterization of cell surface-expressed proteochondroitin sulfate of pre-B Nalm-6 cells and its possible role in laminin adhesion. 866 35

To elucidate possible causes of premature aging seen in a strain of senescence-accelerated prone (SAMP8) mice, levels of murine leukemia virus (MuLV) were quantitated in various tissues of SAMP8 by an SC-1/UV plaque assay. MuLV levels in SAMP8 tissues were compared to those seen in the closely related SAMR1 strain, which is resistant to premature aging. MuLV titers were found to be higher in blood and spleen and much higher in brain of SAMP8 than in the same tissues of SAMR1. MuLV levels were seen to increase in SAMP8 brain with increasing age. Virus typing experiments indicated that the MuLV from SAMP8 brain is N-tropic, as is the MuLV seen in the AKR strain, one of the SAM progenitor strains. MuLV from SAMP8 brain was able to grow well in SAMR1 mouse embryo cells, indicating that it may be possible to infect SAMR1 mice with the SAMP8 MuLV to determine the effects of the virus on aging of SAMR1 mice.
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PMID:Titers of murine leukemia virus are higher in brains of SAMP8 than SAMR1 mice. 939 Jul 82

A series of inbred strains of mice have been developed that are either prone (SAMP) or resistant (SAMR) to accelerated senescence. All of these strains originated from an inadvertent cross or crosses between the AKR/J mouse strain and an unknown strain(s). The characteristics of the nine senescence-prone lines differ, with all strains showing generalized aspects of accelerated aging but with each line having a specific aging-related change that is emphasized, e.g. learning and memory deficits, osteoporosis and senile amyloidosis. The senescence-resistant strains have normal patterns of aging and do not show the specific aging-related changes seen in SAMP strains. The fact that AKR mice have high levels of endogenous, ecotropic murine leukemia virus (MuLV) prompted an examination of the expression levels of MuLV in SAM strains. Analysis of brain, spleen and thymus samples revealed that seven of nine SAMP strains had high levels of MuLV and contained the Emv11 provirus (previously termed Akv1) that encodes the predominant MuLV found in AKR mice. In contrast, none of the SAMR strains had Emv11 or significant amounts of virus. The current findings represent an initial step in determining the role of MuLV in the accelerated senescence seen in SAMP strains.
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PMID:Murine leukemia virus in organs of senescence-prone and -resistant mouse strains. 1185 21

Ganglioside GM3 was reported to induce the differentiation of HL-60 cells to differentiate along the macrophage-monocytic route. We used human monocytoid leukemia J6-2 cells and successfully induced differentiation by GM3. Because differentiation is accompanied by retarded growth rate and cell cycle is intimately related to phospholipid metabolism, so we explored how GM3 was related to phospholipid metabolism. By using [32P]Pi, [3H-CH3]choline, [3H-CH3]SAM, and [3H]inositol as radioactive tracers, we studied the turnover changes of phospholipids and their metabolites induced by GM3. For the morphological changes of differentiation to occur, the cells had to be treated with GM3 at a concentration of 50 microM for 5-6 days, but the phospholipid changes occurred at a very early stage of GM3 treatment (only 1 h). Our results indicate that GM3 stimulated PE methylation pathway inhibited both CDP-choline pathway and PI cycle. The phospholipid changes may constitute the early events in differentiation induced by GM3.
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PMID:Effects of ganglioside GM3 on phospholipid turnover of human leukemic J6-2 cells. 1237 12


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