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 production of interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 3 (IL-3) and granulocyte/macrophage colony stimulating factor (G/M-CSF) by preleukemic and leukemic spleen cells from Balb/c mice infected with Moloney leukemia virus (MoLV) was examined. During the development of the leukemia, the secretion of IL-1 and IL-2 significantly decreased, while the secretion of IL-3 and G/M CSF was not affected and was even enhanced. In addition, a 10 fold increase in the number of colony forming units in cultures (CFU-C) was found in the leukemic spleen indicating a shift in hematopoiesis from the bone marrow (BM) to the spleen. The low levels of IL-2 found in the conditioned medium of Concanavalin A (Con A) activated leukemic spleen cells could not result from active consumption of IL-2 by the cells, pointing to a genuine defect in IL-2 production. This failure of IL-2 secretion could be partially overcome by the addition of phorbol 12 beta-myristate 13 alpha-acetate (PMA) to the cells but not by the addition of IL-1. The defect in IL-2 production and the enhancement in IL-3 and G/M-CSF production may be of significance in the progression of preleukemic cells to autonomous malignant cells.
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PMID:Alterations in lymphokine secretion during leukemogenesis. 305 45

Stable expression of the 40-kDa transactivator protein (Tax) from the type I human T-cell leukemia virus (HTLV-I) in Jurkat T cells leads to the activation and sustained expression of certain cellular genes that are transiently induced during normal T-cell growth. Cellular genes induced by Tax include those encoding the alpha subunit of the high-affinity interleukin 2 receptor (Tac), interleukin 2, and granulocyte/macrophage colony-stimulating factor. Tax induction of the interleukin 2 gene is synergistically amplified by mitogens that augment cytoplasmic levels of calcium. These changes in the pattern of cellular gene expression reflect a specific action of Tax, as they are undetectable in isogenically matched control cell lines expressing antisense tax cDNA. The spectrum of cellular genes regulated by Tax appears to be restricted: several other T-cell genes, either inducibly or constitutively expressed, are unaffected by this viral protein. These cell lines constitutively expressing Tax provide valuable reagents to explore the molecular basis for Tax action and to delineate the full spectrum of cellular genes regulated by this retroviral gene product.
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PMID:Stable expression of the tax gene of type I human T-cell leukemia virus in human T cells activates specific cellular genes involved in growth. 305 51

The erythroleukemia induced in susceptible mice by Friend virus (FV) is a progressive, lethal disease. A variant strain of Friend virus (regressing FV) produces a histopathologically identical leukemia except that the disease spontaneously regresses in 50% of leukemic mice. Normal T-cell and macrophage function are required for regression to occur and in animals that are going to regress, specifically reactive T-cells are found in the spleen. Passive transfer of sensitized T-cells from regressing FV immunized or regressed mice caused regression of the conventional lethal leukemia induced by FV. To expand the effector cell populations, characterize them and improve their therapeutic efficacy, sensitized T-cells were cultured in vitro. The T-cells, isolated from regressed or immunized mice, were grown and expanded in vitro with interleukin 2 and antigen (mitomycin C treated regressing FV-infected cell lines). The T-cells demonstrated high levels of in vitro cytotoxicity against FV antigens but exhibited no blastogenic response to the same antigens. When fully FV-induced leukemic mice (14 days post virus inoculation; spleen weight, greater than 0.75 g) were given one injection of 5 X 10(6) in vitro cultured T-cells and no other treatment the mice experienced permanent regressions of their disease. From T-cell cultures depleted of specific cell populations with monoclonal antisera, helper Lyt-1+ cells were shown to be responsible for permanent regressions (cures), whereas cytotoxic Lyt-2+ cells caused temporary leukemia remissions. This model thus provides an experimental system of highly effective passive cellular immunotherapy against an autochthonous, fully developed leukemia, requiring no adjunctive treatment for activity.
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PMID:Induction of leukemia regression in mice by immunotherapeutic transfer of T-lymphocytes. 307 85

Anti-Tac, a monoclonal antibody directed to the human interleukin 2 (IL-2) receptor, has been successfully conjugated to the alpha-particle-emitting radionuclide bismuth-212 by use of a bifunctional ligand, the isobutylcarboxycarbonic anhydride of diethylenetriaminepentaacetic acid. The physical properties of 212Bi are appropriate for radioimmunotherapy in that it has a short half-life, deposits its high energy over a short distance, and can be obtained in large quantities from a radium generator. Antibody specific activities of 1-40 microCi/microgram (1 Ci = 37 GBq) were achieved. Specificity of the 212Bi-labeled anti-Tac was demonstrated for the IL-2 receptor-positive adult T-cell leukemia line HUT-102B2 by protein synthesis inhibition and clonogenic assays. Activity levels of 0.5 microCi or the equivalent of 12 rad/ml of alpha radiation targeted by anti-Tac eliminated greater than 98% the proliferative capabilities of HUT-102B2 cells with more modest effects on IL-2 receptor-negative cell lines. Specific cytotoxicity was blocked by excess unlabeled anti-Tac but not by human IgG. In addition, an irrelevant control monoclonal antibody of the same isotype labeled with 212Bi was unable to target alpha radiation to cell lines. Therefore, 212Bi-labeled anti-Tac is a potentially effective and specific immunocytotoxic reagent for the elimination of IL-2 receptor-positive cells. These experiments thus provide the scientific basis for use of alpha-particle-emitting radionuclides in immunotherapy.
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PMID:Bismuth-212-labeled anti-Tac monoclonal antibody: alpha-particle-emitting radionuclides as modalities for radioimmunotherapy. 307 13

Large granular lymphocyte (LGL) leukemia is a rare disease characterized by clonal expansion of LGL associated with chronic neutropenia, multiple auto-antibodies, and occasionally polyarthritis. We studied cell surface antigen expression and functional activity of leukemic LGL from ten such patients. Using two-color flow cytometric analysis, we found that leukemic LGL from all ten patients expressed the CD3 and HNK-1 markers, while cells from only four patients expressed IgG Fc receptors (FcR). The LGL leukemic cells had little or no NK activity (defined as MHC-nonrestricted cytotoxicity against K562 target cells); however, NK activity could be induced in leukemic LGL by in vitro treatment with as little as 0.05 microgram/mL of anti-CD3 monoclonal antibody. Cell sorting experiments demonstrated that NK activity was induced in CD3+ leukemic LGL (either CD3+, HNK-1+ or CD3+, FcR+) with anti-CD3 monoclonal antibody but not in normal CD3+, FcR- T cells. Treatment with purified interleukin 2 (IL 2) also caused direct activation of some CD3+ leukemic LGL. Despite induction with anti-CD3 MAb or IL 2, activated leukemic LGL did not proliferate or express high density IL 2 receptors detectable by cell sorter analysis. Treatment with alpha interferon had minimal effect on NK activity of LGL leukemic cells. These results suggest that leukemic LGL may provide a useful model for examining the signals required for LGL maturation and activation.
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PMID:Induction of NK activity in large granular lymphocyte leukemia: activation with anti-CD3 monoclonal antibody and interleukin 2. 309 27

The interleukin 2 (IL-2) receptor system plays a key role in the T-cell immune response. Although IL-2 binding was reported to be restricted to the Tac peptide, we have identified an IL-2 binding peptide that does not react with anti-human IL-2 receptor monoclonal antibodies, including anti-Tac on MLA 144, a gibbon ape T-cell line. The MLA 144 cell line expressed 6800 IL-2 binding sites per cell with a low (Kd = 14 nM) affinity for human recombinant IL-2. Using cross-linking methodology, we demonstrated that the IL-2 binding peptide on MLA 144 is larger (Mr 75,000) than the Tac peptide, which has a Mr of 55,000. An IL-2 binding peptide of similar size (Mr 75,000) was also identified in addition to the Tac peptide (Mr 54,000-57,000) on Hut 102, a human T-cell lymphotrophic virus I-induced T-cell leukemia line, and phytohemagglutinin-activated normal human and gibbon ape lymphoblasts. Anti-Tac antibody did not block the binding of 125I-labeled IL-2 to MLA 144 cells. However, this antibody abolished the binding of 125I-labeled IL-2 not only to the Tac peptide on Hut 102 cells and normal lymphoblasts but also to the Mr 75,000 IL-2 binding peptide, suggesting that this latter peptide is associated with the Tac peptide to form the high-affinity IL-2 receptor complex.
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PMID:Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in a multichain interleukin 2 receptor complex. 309 89

The aim of the current study was to determine the ability of antigen-driven cloned helper cell independent cytotoxic T lymphocytes (HITc) to proliferate and to survive in vivo and to mediate tumor therapy. The HITc clone utilized (denoted 1.B6) was specifically cytolytic to FBL-3, a syngeneic Friend virus-induced murine leukemia. Activation in vitro (48 hr) with FBL-3 induced secretion of interleukin 2 (IL 2), expression of IL 2 receptors (IL 2R), and in vitro proliferation. These cells could be "rested" for several weeks without stimulation, which resulted in reduced expression of IL 2R; however, restimulation with antigen resulted in reinduction of IL 2R and proliferation. The ability of cloned HITc to proliferate and to survive in vivo was examined in cyclophosphamide (CY) pretreated donor mice congenic for the Thy-1 gene. Adoptively transferred cloned HITc could be found in large numbers, and were widely distributed in vivo 1 wk after transfer. In tumor therapy, 1.B6 cells when injected into a site of tumor (i.p.) and used as an adjunct to CY were effective against disseminated FBL-3. In this circumstance, cloned 1.B6 cells could be recovered from cured mice 125 days after transfer and were shown to specifically lyse tumor and proliferate in vitro in response to FBL-3. Thus as an adjunct to CY, tumor-specific cloned HITc are capable of eradicating disseminated leukemia, persisting long-term in vivo, and providing specific immunologic memory.
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PMID:Antigen-driven T cell clones can proliferate in vivo, eradicate disseminated leukemia, and provide specific immunologic memory. 310 81

The functional importance of interleukin 2 (IL-2) receptors in the regulation of malignant B cell proliferation still remains to be clarified. We studied malignant CLL B cells for the presence of IL-2 receptors and responsiveness to IL-2 with respect to proliferation and B cell colony formation. Seven of 25 B-cLL patients studied had reactivity for anti-Tac (mean, 11.8%; range 4-31%). Purified control T cells expressed less than 2% reactivity to anti-Tac. CLL B cell colony forming cells were reactive with anti-Tac in all five patients studied (mean, 24.8%; range, 17-31%). The proliferative response of control and CLL B cells to both a partially purified preparation of IL-2 and recombinant IL-2 (rIL-2) was also examined. Control B cells demonstrated a dose-dependent, enhanced proliferative response to IL-2. At lower IL-2 concentrations (2-200 units/ml), rIL-2 appeared to have a more significant proliferative enhancing effect on control B cells than did the partially purified IL-2 preparation. In contrast, no concentration of the IL-2 preparations enhanced CLL B cells' proliferative response. The monoclonal antibody anti-Tac was capable of inhibiting control B cell responsiveness to IL-2, rIL-2 did not support CLL B cell colony formation. Thus, malignant B cell populations may spontaneously express the Tac antigen in the absence of a functional response to IL-2. The significance of this in the treatment of lymphomas is underscored by the development of new therapeutic strategies which would seek to incorporate the use of immunoregulatory lymphokines such as IL-2.
Leukemia 1987 Feb
PMID:Malignant chronic lymphocytic leukemia B cells express interleukin 2 receptors but fail to respond to interleukin 2's proliferative signal. 311 4

The macrocyclic lactone bryostatins, isolated from marine bryozoans, have been found to be strong inhibitors of e.g., the P 388 murine lymphocyte leukemia cell line and in vivo systems. Presently, bryostatin 1 is under preclinical development as a potential anticancer drug, although the bryostatins exhibit some of the same biological effects as the tumor promoting phorbol-12-myristate-13-acetate (PMA), especially activation of protein kinase C in certain cell types. In our experiments, we investigated the influence of bryostatin 1 on the synthesis of interleukin 2 (IL2) and interferon-gamma (IFN-gamma) by ionophore A23187 or mitogen-induced human blood lymphocytes. These results were then compared with those achieved using the two tumor promotors PMA and teleocidin. Our data indicate that bryostatin 1 is comparable to these two other drugs in increasing production of the two lymphokines 10-100-fold. The IL2 and IFN-gamma production kinetics of cultures induced with either A23187/bryostatin 1 or A23187/PMA were practically identical. The general pattern of peptides, however, released from bryostatin 1 coinduced cultures differed from that obtained when PMA was used.
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PMID:Co-induction of lymphokine synthesis by the antineoplastic bryostatins. 312 67

We report here experiments on the analysis of cellular signal transduction in a series of patients with chronic B cell disorders (B cell chronic lymphocytic leukemia [B-CLL] and prolymphocytic leukemia). We compared the response of the leukemic cells with primary external signals (interleukin 2 [IL-2] or B cell differentiation factors [BCDF or IL-6]) with their response to secondary inducers (the phorbol ester (12-O-tetradecanoylphorbol-13-acetate [TPA] or the calcium ionophore A23187) that circumvent the first part of the signal transduction pathway by directly activating the key enzyme protein kinase C. One BCDF was synthesized by mitogen-activated peripheral blood B lymphocytes; a second BCDF was constitutively produced by the human bladder carcinoma cell line T24. Changes in morphology, Tac (IL-2 receptor) expression, RNA synthesis measured by 3H-uridine uptake, and immunoglobulin production tested by enzyme-linked immunosorbent assay were used as parameters of successful signal transduction. TPA alone and TPA plus A23187 (synergistically) effectively initiated differentiation in all the leukemia cases. Neither IL-2 nor BCDF (singly or in combinations) caused equivalent responses. On the other hand, IL-2 and BCDF produced a substantial differentiation effect on normal B lymphocytes. Our data suggest that (a) B-CLL cells are able to respond to direct stimulation of the second messenger pathway (through protein kinase C) but not to the physiological stimuli IL-2 or BCDF; (b) the defect in signal transduction appears to be located upstream of protein kinase C (a possible candidate is a G protein); (c) malignant B cells may spontaneously or after treatment with inducers express the IL-2 receptor (Tac antigen) in the absence of a functional differentiating response to IL-2; and (d) signs of proliferation/differentiation in B-CLL samples after incubation with IL-2 or BCDF might be due to contamination of the cell populations with residual normal B cells.
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PMID:Analysis of signal transduction in B chronic lymphocytic leukemia cells. 312 49


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