Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of the human myelomonocytic U937 and THP1 cell lines for 24 h with 180 mM of the differentiation inducer DMSO, resulted in priming these cells to subsequent LPS-induced cytolysis. The observed cytotoxicity was LPS dose-dependent and characterized by a prolonged lag phase with detectable effects only appearing after 8 h. LPS-induced apoptotic cell death in DMSO-pretreated U937 cells as indicated by the appearance of 200 basepair DNA fragments upon agarose gel electrophoresis of total cellular DNA. Furthermore, DMSO pretreatment potentiated the cells' capacity to produce cytokines, especially TNF, upon LPS stimulation. This endogenously present TNF was metabolized by the cells. These observations suggested that the LPS-induced cytostasis/cytotoxicity was mediated through TNF. Indeed, medium conditioned by LPS-stimulated U937-DMSO cells was found to exert a cytotoxic effect on U937-DMSO cells that was completely neutralized by anti-human TNF antiserum. Such TNF-like activities were not only present in the supernatant but also at the level of the cell membrane of LPS-stimulated U937-DMSO cells. Apart from TNF, other exogenously applied recombinant cytokines (IL1, IL6, IFN gamma, GM-CSF) were not cytotoxic to U937-DMSO cells. Thus, DMSO-pretreated myelomonocytic cells become sensitive to LPS-induced cytotoxicity, which is, at least in part, mediated through endogenous TNF.
Leukemia 1994 Nov
PMID:Polar agents with differentiation-inducing capacity prime myelomonocytic cell lines to lipopolysaccharide-induced cytolysis: the role of endogenous tumor necrosis factor. 796 41

We evaluated eosinophils morphology, physical properties and antileukemic activity in autologous bone marrow transplanted (ABMT) patients treated with subcutaneous recombinant interleukin 2 (rIL-2) and recombinant human interferon alpha 2a (IFN alpha) given as outpatient immunotherapy. All patients receiving rIL-2/IFN alpha therapy developed peripheral blood eosinophilia of 20-40% peaking at 2-4 weeks of therapy. While on rIL-2/IFN alpha therapy the eosinophils became hypodense and hypersegmented. The antibody dependent cell-mediated cytotoxic activity (ADCC) of the eosinophils against the human B-cell lymphoma cell line (Raji) was depressed post-ABMT. Prolonged (28 days) in vivo rIL-2/IFN alpha immunotherapy enhanced ADCC activity of the eosinophils and brought them to normal levels. Similarly, rIL-2/IFN alpha immunotherapy enhanced the depressed cytotoxic activity of neutrophils post-ABMT to normal levels. Thus, eosinophils and neutrophils from rIL-2/IFN alpha-treated ABMT recipients may be targeted toward tumor cells by antibody, and express tumoricidal activity. No effect of rIL-2/IFN alpha was observed on monocyte-dependent ADCC activity which remained normal post-ABMT. We conclude that in addition to their effect on lymphocytes, cytokine-mediated immunotherapy consisting of subcutaneous low doses of riL-2 and IFN alpha may mediate their therapeutic effects in cancer therapy by increasing the number of eosinophils and enhancing the antitumor activity of eosinophils and neutrophils, provided that tumor-specific or tumor-associated antibodies are present.
Leukemia 1994 Aug
PMID:Eosinophils activation in post-autologous bone marrow transplanted patients treated with subcutaneous interleukin-2 and interferon-alpha 2A immunotherapy. 805 77

In view of cellular immunotherapy with cytotoxic monocytes in minimal residual leukemia we have studied the effects of monocytes on the growth and survival of leukemic cells from cell lines and from patients with acute myeloid leukemia (AML). Using highly purified and interferon-gamma (IFN gamma) activated human monocytes, monocyte-mediated cytotoxicity (MMC) was evaluated in an MTT-based colorimetric cytotoxicity assay against six human leukemic cell lines (U937, THP1, KG1, K562, HL60, and 1,25(OH)2D3 differentiated HL60 cells) and cells from AML patients. Leukemic cells from cell lines with an immature phenotype were found to be resistant to MMC, whereas leukemic cells with a more mature and monocytic phenotype were sensitive. This paralleled the sensitivity to tumor necrosis factor-alpha (TNF-alpha). AML cells from patients with an immature phenotype (FAB-M1/M5A) were significantly less sensitive to MMC as compared to more mature AML cells (FAB-M2/M4/M5B). The growth stimulatory effects of non-activated monocytes on immature AML cells could be abrogated in the presence of IFN gamma or IL-3 and GM-CSF. In addition, these cytokines further potentiated MMC, preferentially affecting cells with a more mature phenotype. AML cells with an immunologically immature phenotype (CD34(high), HLA-Dr(low), CD13(low), CD14(low)) were revealed as the least sensitive cells to MMC. The growth stimulatory effects of IL-3/GM-CSF with or without TNF-alpha on AML cells correlated with resistance to MMC. In addition, the cytolytic effects of TNF-alpha in the presence of IFN gamma correlated with an increased susceptibility of AML cells to MMC. In conclusion, our data strongly indicate that MMC is related to maturation in AML, which is correlated to the differential stimulatory and cytolytic effects of monocyte-derived cytokines such as IL-3, GM-CSF, and TNF-alpha.
Leukemia 1994 Aug
PMID:Maturation-dependent susceptibility to monocyte-mediated cytotoxicity in acute myeloid leukemia. 805 79

The cell line described here was established for a 50-year-old male patient with rapidly progressive non-Hodgkin's lymphoma whose marrow was diffusely infiltrated with large granular lymphocytes (LGL). Immunophenotyping of marrow blasts and peripheral lymphocytes was positive for CD56, CD2 and CD7, and negative for CD3. Cytotoxicity of peripheral blood mononuclear cells at an effector: target (E:T) cell ratio of 50:1 was 79% against K562 cells and 48% against Daudi cells. To establish the line, cells from the peripheral blood were placed into enriched alpha medium containing 12.5% fetal calf serum, 12.5% horse serum, 10(-4) M beta-mercaptoethanol and 10(-6) M hydrocortisone. Growth of the line (termed NK-92) is dependent on the presence of recombinant IL-2 and a dose as low as 10 U/ml is sufficient to maintain proliferation. Conversely, cells die within 72 h when deprived of IL-2; IL-7 and IL-12 do not maintain long-term growth, although IL-7 induces short-term proliferation measured by 3H-thymidine incorporation. None of the other cytokines tested (IL-1 alpha, IL-6, TNF-alpha, IFN-alpha, IFN-gamma) supported growth of NK-92 cells which have the following characteristics: surface marker positive for CD2, CD7, CD11a, CD28, CD45, CD54, CD56bright; surface marker negative for CD1, CD3, CD4, CD5, CD8, CD10, CD14, CD16, CD19, CD20, CD23, CD34, HLA-DR. DNA analysis showed germline configuration for T-cell receptor beta and gamma genes. CD25 (p55 IL-2 receptor) is expressed on about 50% of all cells when tested at 100 U/ml of IL-2 and its expression correlates inversely with the IL-2 concentration. The p75 IL-2 receptor is expressed on about half of the cells at low density irrespective of the IL-2 concentration. NK-92 cells kill both K562 and Daudi cells very effectively in a 4 h51-chromium release assay (84 and 86% respectively, at an E:T cell ratio of 5:1). The cell line described here thus displays characteristics of activated NK-cells and could be a valuable tool to study their biology.
Leukemia 1994 Apr
PMID:Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells. 815 60

In summary, it can be expected that the availability of unrelated donors will increase the number of CML patients that can be treated curatively with allogeneic BMT. Hydroxyurea has replaced busulfan as first line treatment in CML since it prolongs survival. Ongoing randomized studies comparing IFN-based treatment regimens with standard chemotherapy or IFN-monotherapy probably will answer the question whether IFN can cure a small percentage of CML patients and whether this small percentage can be increased by additional chemotherapy. The present attempts to improve prognostic scores and to apply them to early treatment decisions will allow treatment adaptation more individually. The implications of endogenous retroviral sequences expressed in CML cells are not known now, but may be far reaching.
Leukemia 1994 Apr
PMID:Therapeutic progress and comparative aspects in chronic myelogenous leukemia (CML): interferon alpha vs. hydroxyurea vs. busulfan and expression of MMTV-related endogenous retroviral sequences in CML. German CML Study Group. 815 79

The correlation between virus induced NF-kappa B DNA binding activity and interferon gene expression was examined in the myelomonoblastic PLB-985 cell line. Previous studies have shown that chronic HIV-1 infection of PLB-985 cells (PLB-IIIB) leads to the selection of cells with a more differentiated monocytic phenotype and with constitutive NF-kappa B DNA-binding activity. In this report we demonstrate that the kinetics of HIV-1 and Sendai virus infection of PLB-985 cells directly correlates with induction of NF-kappa B DNA binding activity. Based on UV cross-linking and immunoprecipitation analysis, p50, the strong transcriptional activator p65 and c-Rel represent the major constituents of this NF-kappa B DNA-binding activity. We also demonstrate an alteration in the kinetics of type I IFN gene transcription following secondary Sendai virus infection of PLB-IIIB cells compared to PLB-985. The results of our studies suggest that HIV infected individuals may respond differently to secondary viral or bacterial infections by augmenting the synthesis of NF-kappa B regulated immune response modifiers, which could alter the onset or progression of AIDS.
Leukemia 1994 Apr
PMID:Virus induction of NF-kappa B/Rel proteins and type I interferon gene expression in myelomonoblastic cells. 815 86

Leukemic cells from most cases of acute lymphoblastic leukemia (ALL) rapidly die by apoptosis in vitro, unless they are cultured onto bone marrow-derived stromal layers. We have recently established a stroma-supported tissue culture technique that allows long-term culture of leukemic lymphoblasts. In this study, we used this technique to examine interferon alpha (IFN alpha) cytotoxicity to ALL blasts. In 16 ALL cases tested (14 B-lineage ALL, 2 T-ALL), the number of cells recovered after 7 days of culture on stromal feeder layers was 60-178% (median, 108%) of those originally seeded. The percentage of lymphoblasts killed by 2000 U/ml IFN alpha 2b after 7 days of culture, ranged from < 1% to 91% (median, 56%). Cytotoxicity was (i) dose-dependent, (ii) eliminated by a neutralizing antibody to IFN alpha, and (iii) accompanied by tyrosine phosphorylation of a 135 kDa protein, which was detectable after 5 minutes of treatment. Numbers of residual normal lymphoid cells in the cultures remained low and conditioned medium prepared from IFN alpha-stimulated T, NK, and stromal cells was not cytotoxic to ALL blast cells. In contrast to results in freshly isolated ALL cells, six ALL cell lines tested were completely resistant to IFN alpha cytotoxicity. We conclude that IFN alpha is directly cytotoxic in most ALL cases but that the intensity of its effects varies widely among cases. The method used in this study may be applied to evaluate leukemic blast cell sensitivity to compounds with potential antileukemic activity, and to select patients to be entered in to clinical trials.
Leukemia 1993 Dec
PMID:Use of stroma-supported cultures of leukemic cells to assess antileukemic drugs. I. Cytotoxicity of interferon alpha in acute lymphoblastic leukemia. 825 98

To improve the management of chronic myeloid leukemia (CML) in a single center, we used interferon alpha (IFN alpha) to treat newly diagnosed CML patients and investigated the factors predictive of a major cytogenetic response. Fifty-two patients (pts) with a median age of 51.5 years (16-68), were given interferon alpha (IFN alpha) (5 millions/m2/day, subcutaneously). The median interval between diagnosis and IFN alpha was 41.5 days (0-160). The doses of INF alpha were adjusted to maintain the white blood cell (WBC) count between 1.5 and 5 x 10(9)/l and the platelet count between 50 and 100 x 10(9)/l. At diagnosis, Sokal's criteria were used to classify patients into three groups: low (n = 24), intermediate (n = 19) and high risk (n = 9). A complete hematological response (CHR) was achieved in 42 cases (80.7%). A partial response was present in nine; only one patient did not respond. By multivariate logistic regression analysis, only the age at diagnosis was found to influence the CHR rate (P = 0.06). Cytogenetic response was evaluated in 46 responder patients. Twenty-three patients achieved a major cytogenetic response (MCR) which was either partial ( > or = 65% pH negative cells) (n = 3) or complete (CCR) (n = 20). By univariate analysis, two disease-related variables were found to influence the MCR rate in 40 evaluable CHR patients: spleen size at diagnosis and peripheral blood blast percentage. However, using either univariate or multivariate analysis, the most significant factor was the achievement of CHR within 3 months (P < 0.0004 and P < 0.0002, respectively). These results show that IFN alpha can induce high rates of hematological and cytogenetic responses when administered in doses leading to myelosuppression. The achievement of CHR within 3 months could be useful to identify early, those patients who will not respond to IFN alpha and who need alternative treatments such as allogeneic or autologous stem cell transplantation.
Leukemia 1995 Dec
PMID:Response to recombinant interferon alpha in patients with chronic myelogenous leukemia in a single center: results and analysis of predictive factors. 860 8

PML has been identified through its fusion to the RAR alpha gene in acute promyelocytic leukemia (APL). The PML protein is specifically associated to nuclear bodies (NBs) whose alterations in APL were proposed to contribute to leukemogenesis. The role of this nuclear domain (which also harbors the Sp100 autoantigen and the NDP52 protein) is unknown. Here, we show that the PML protein, like Sp100 and NDP52, is induced by interferons (IFNs alpha, beta and gamma) in a large variety of human cells. Interestingly, the NBs that contain the three IFN-induced proteins appear to be associated to speckles labelled by the IFN-mediator Mx1. These observations link NBs to IFN response pathways, which may contribute to the elucidation of the biological role of these structures. In APL cells, IFNs induced both PML and PML/RAR alpha expression, resulting in an increased sequestration of PML and RXRs in the microspeckles induced by the fusion protein. As PML has growth suppressing properties, it may mediate some of the antiproliferative effects of IFN. In APL, inactivation of PML may result in disruption of growth control.
Leukemia 1995 Dec
PMID:Induction of the PML protein by interferons in normal and APL cells. 860 13

We studied the natural killer (NK) cell activity and in vitro production of the cytokines which can enhance NK activity (interleukin-1 beta (IL-1 beta), interferon gamma (IFN gamma), and interleukin-2 (IL-2)) after stimulation in 44 patients with acute leukemia (AL) and 14 normal controls. We also studied the influence of these parameters on relapse and the relapse-free survival (RFS) (after the date of assay) of the AL patients. The NK activity and the production of cytokines in the peripheral blood mononuclear cells (PBMNC) from 16 patients at the untreated or relapsed stage as well as from 12 patients after consolidation were significantly lower than those from controls (both P<0.01), and those from the 16 patients at maintenance or off treatment were also significantly lower than those from the controls (P<0.01 or P<0.05). RFS after the date of assay of the patients in remission with NK activity above the median value was significantly longer than that of the patients below the median (P<0.05). The production of cytokines in the PBMNC from patients who showed continuous complete remission for at least 6 months was higher than that from the patients who relapsed early. These findings suggest that impaired NK cell function and cytokine production are associated with early relapse of AL regardless of remission status.
Leukemia 1996 Mar
PMID:Natural killer cell activity and cytokine production as prognostic factors in adult acute leukemia. 864 65


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