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 p53 tumor suppressor gene plays a role in controlling a G1 phase checkpoint. The WAF1/CIP1 gene with encodes p21WAF1/CIP1 protein, an inhibitor of cyclin-dependent kinases, is a downstream mediator of p53 function. We examined expression of the WAF1/CIP1 gene and its relationship to growth arrest and differentiation in p53-null human leukemic cell lines. We show that p53-independent induction of WAF1/CIP1 occurs in human leukemia cells treated with 12-O-tetradecanoylphorbol-13-acetate, okadaic acid, or IFN-gamma but not with retinoic acid, vitamin D3, or DMSO. Furthermore, WAF1/CIP1 induction correlates with growth arrest associated with monocyte-macrophage differentiation. The present studies support the idea that WAF1/CIP1 gene expression can be regulated through multiple mechanisms, suggesting that strategies may be designed to restore the G1 checkpoint controls in p53-null cells by targeting these p53-independent mechanisms of WAF1/CIP1 induction.
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PMID:p53-independent induction of WAF1/CIP1 in human leukemia cells is correlated with growth arrest accompanying monocyte/macrophage differentiation. 783 38

Human myeloid leukaemia cell lines have been shown to differentiate into distinct cell lineages in vitro in response to several differentiation-inducing agents. A human eosinophilic leukaemia cell line, EoL-1, has been shown to differentiate into mature eosinophilic granulocytes by treatment with the culture supernatant of a human T-cell line, HIL-3. In this study we have studied whether the EoL-1 cell line has potential to differentiate into cell lineage other than eosinophils. We found that EoL-1 cells cultured in the presence of tumour necrosis factor (TNF)-alpha (10 u/ml) and interferon (IFN)-gamma (1000 u/ml) for 2-4 d differentiated into macrophage-like cells in morphology, and expressed CD14 antigen on their cell surface. It is possible that the small subpopulation of EoL-1 cells which contains non-specific esterase (NSE) activity may be preferentially differentiated by TNF-alpha and IFN-gamma. To clarify this issue, we have cloned the EoL-1 cell line and obtained NSE negative and positive sublines. Both EoL-1 sublines differentiated into monocyte/macrophage-like cells, because: (a) EoL-1 sublines were induced to express CD14 antigen, and (b) they attached firmly to the plastic wells; (c) after differentiation they became strongly positive for NSE staining, and secreted TNF-alpha in response to the stimulation with lipopolysaccharide; and (d) they exhibited potent phagocytic activity. Therefore, we found that the EoL-1 cell line has the ability to differentiate not only into mature eosinophilic cells but also into monocyte/macrophage cell lineage, suggesting that EoL-1 cells represent immature cells with ability to differentiate into multiple cell lineages.
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PMID:Induction of differentiation into monocyte/macrophage cell lineage of a human eosinophilic leukaemia cell line EoL-1 by simultaneous stimulation with tumour necrosis factor-alpha and interferon-gamma. 787 75

Donor marrow transplantation can cure chronic myelogenous leukemia (CML). Unfortunately, the procedure is associated with severe complications and is limited to the minority of potential recipients with suitably matched donors. Autologous marrow transplantation using negative selection approaches such as incubation with gamma interferon (IFN-gamma) can produce cytogenetic and clinical remissions, but they are often associated with recurrent evidence of leukemia. A primitive progenitor population can be separated from normal human marrow on the basis of morphologic characteristics and cell surface antigen expression. Cell populations with similar morphologic and phenotypic characteristics obtained by positive selection from the marrow of patients with CML appear to be benign. Benign primitive and committed progenitors selected in this fashion can be expanded ex vivo when cultured in a "Transwell" system which physically separates hematopoietic cells from stromal feeder layers. Positive selection and ex vivo cultivation of benign progenitors from CML marrow may provide a source of hematopoietic stem cells suitable for autologous marrow transplantation. Autologous natural killer (NK) cells obtained from the peripheral blood of patients with CML are of benign origin and have antileukemia activity. Interleukin 2 (IL-2) activated autologous NK cells may be used in post-transplant cellular therapy to prevent recurrence of CML.
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PMID:Chronic myelogenous leukemia: in search of the benign hematopoietic stem cell. 790 18

Cutaneous lesions of T-cell proliferative disorders are characterized by epidermotropic infiltration of the neoplastic cells and expression of intercellular adhesion molecule-1 (ICAM-1) and HLA-DR by lesional keratinocytes. Using cloned HTLV-1-infected T-cells obtained from patients with adult T-cell leukemia (ATL), we have studied immunobiological activities of cytokines released from the T-cell lines and their ability to adhere to cultured keratinocytes. Three out of the five CD-4-positive, HTLV-1-infected T-cell clones secreted both IFN-gamma and IL-4, similar to murine Th0 clones. The other two clones did not produce such cytokines. ICAM-1 and HLA-DR molecules were induced on cultured normal human keratinocytes and organ-cultured skin specimens by co-cultivation with IFN-gamma-producing T-cell clones or their culture supernatants. Induction of both molecules was markedly inhibited by pretreatment of the supernatants with excess amounts of anti-IFN-gamma monoclonal antibody. The number of cells adherent to the normal cultured keratinocytes was greater in the IFN-gamma-producing clones than in the non-producing ones. These data suggest that some HTLV-1-infected clones produce cytokines, including IFN-gamma, which in turn induce ICAM-1 on keratinocytes, thereby enhancing the ability of the T-cell clones to adhere to the keratinocytes.
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PMID:Induction of intercellular adhesion molecule-1 and adherence of HTLV-1-infected T-cells to cultured keratinocytes. 791 43

AKR/J mice, highly susceptible to spontaneous T cell leukemogenesis, were protected from developing the disease by H-2-compatible allogenic bone marrow transplantation (BMT) and intermittent treatment with interleukin-2(IL-2). Allogeneic BMT from C3H/HeJ mice and treatment with PBS yielded T cell leukemia in chimeras after the same latent period as that observed in normal AKR/J mice. In contrast, IL-2-treated chimeras caused an incidence of only 40% T cell leukemia. The preventing effect of IL-2 on leukemia development was not observed in one-year-treated chimeras, probably due to a lack of continuous antileukemic effects over the long term. Both LAK and NK activities in spleen cells were significantly increased in IL-2-treated chimeras. The cytotoxicity against T cell lymphoma cell line derived from AKR/J also increased in the IL-2-treated chimeras. Similarly, LPS-, PWM-, and IL-2-induced responses were increased in the IL-2-treated chimeras. TNF-alpha secretion from spleen cells also rose after IL-2-administration. IL-1 beta, IFN-gamma, and TNF-alpha mRNA became detectable in spleen cells using the PCR technique. The characteristics of leukemia cells in chimeras with overt leukemia were not directly affected by IL-2 administration. It is suggested that partial inhibition of spontaneous T cell leukemia development in AKR/J mice by allogeneic BMT and IL-2 may be due to the enhancement of graft-versus-leukemia effects. Further study may provide insights into the mechanisms involved in preventing leukemia development after allogenic BMT and IL-2 in AKR/J mice.
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PMID:Antileukemic effect of interleukin-2 on spontaneous development of leukemia after H-2-compatible allogenic bone marrow transplantation in AKR/J mice. 792 84

T cells in multiple myeloma (MM) patients are highly susceptible to activation with the anti-CD3 monoclonal antibody (mAb) OKT3. When short-term OKT3 stimulation is carried out on bone marrow mononuclear cells (BMMC), large numbers of CD3+ CD25+ HLA-DR+ cells are rapidly generated and autologous malignant plasma cells are killed. OKT3 may thus be exploited in autologous bone marrow transplantation (ABMT) to purge residual plasma cells and simultaneously activate T cells to induce graft-versus-leukemia-like (GVL-like) activity upon reinfusion. However, the possible impact of ex-vivo short-term OKT3 stimulation on haematological recovery is unknown. The aim of this work was to investigate the effect of OKT3 stimulation in vitro on autologous haemopoietic progenitor cells (HPC) of MM patients. Colony formation by granulocyte-macrophage progenitor cells (granulocyte-macrophage colony-forming units, CFU-GM) was highly suppressed, although supernatants of OKT3-activated T cells contained up to 2,500 pg/ml of granulocyte-macrophage colony-stimulating factor (GM-CSF). T cell depletion completely prevented this suppression. Neutralizing antibodies against TNF-alpha, TNF-beta and IFN-gamma (which are also produced by OKT3-activated MM T cells) did not prevent it, and Transwell cultures showed that cell-to-cell contact was the main mechanism involved. OKT3-activated T cells also suppressed erythroid burst-forming units (BFU-E) and CFU-GM generation from HPC responsible for long-term maintenance of in vitro myelopoiesis. When tested on normal allogeneic BM, MM supernatants of OKT3-stimulated BMMC partially suppressed the generation of day 7 CFU-GM, but had no effect on day 14 CFU-GM. These data indicate that short-term stimulation of BMMC with OKT3 can be used to generate anti-tumour effector T cells for autologous adoptive immunotherapy. It is not a feasable approach for ex-vivo purging and activation procedures in ABMT because of its potent inhibition of autologous haemopoiesis.
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PMID:Generation of anti-tumour activity by OKT3-stimulation in multiple myeloma: in vitro inhibition of autologous haemopoiesis. 799 89

Human bone marrow transplantation is becoming more common in the treatment of certain forms of cancer despite the scarcity of HLA matched donors. Because human umbilical cord blood (HUCB) has been used as a source for stem cells in bone marrow transplantation, and because NK cells appear to be important in graft versus leukemia response, we investigated the lytic activity of freshly isolated HUCB NK cells (HUCB-NK) against tumor targets and their ability to differentiate into LAK cells following stimulation with various cytokines. Although cytotoxicity mediated by fresh HUCB-NK was low compared to that of adult peripheral blood lymphocyte-derived NK cells (PBL-NK), the ability of HUCB-NK to bind to K562 target cells (TC) was similar to PBL-NK. In addition, the PBL-NK cytotoxicity of postpartum mothers was also low compared to that of normal adult PBL-NK. When we incubated HUCB for 18 hr in either IL-2 or IL-12, we boosted the level of HUCB-NK cytotoxicity to approximately the level observed in PBL-NK and increased the level of perforin, granzyme A, and granzyme B mRNA expression. In addition, when we incubated HUCB in IL-2, IL-4, IL-7, IL-12, TNF-alpha, IFN-alpha, IFN-gamma, or TGF-beta for 5 days, we observed that HUCB was capable of generating LAK cells only when incubated with either IL-2 or IL-12. In contrast, IL-2, IL-7, IL-12, TNF-alpha, and IFN-gamma all generated LAK cells from adult PBL. When we added to the medium low-dose IL-2 and irradiated K562 as feeder cells (mini-LAK), we were unable to generate LAK activity from HUCB-NK, whereas we could generate it with PBL-NK cells under the same conditions. Addition of serum derived from HUCB in a 4-hr 51Cr release assay with PBL-NK as the effector cells (EC) and K562 as the TC resulted in a 42% decrease in PBL-NK-mediated cytotoxicity. Although we detected no TGF-beta in HUCB serum, we did detect high concentrations of soluble class I MHC (sHLA). To our knowledge, sHLA has not previously been shown to inhibit NK cytotoxicity, although the expression of class I HLA on the surface of TC has been shown to inhibit NK cytotoxicity. To study further the effect of sHLA on cell-mediated cytotoxicity, we added various concentrations of sHLA to EC mediating NK, ADCC, and CTL activities. All were inhibited in a dose-dependent manner.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The lack of NK cytotoxicity associated with fresh HUCB may be due to the presence of soluble HLA in the serum. 799 57

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

The 5' terminal flanking region of the interferon-inducible gene, 202, contains an interferon-stimulable response element (ISRE), called a GA box, that confers inducibility by interferon(IFN)-alpha, but not by IFN-gamma, on a reporter gene, such as the chloramphenicol acetyltransferase (CAT). Nuclear extracts from L1210 murine leukemia cells, stimulated for various periods of time with IFN-alpha, were mixed with 32P-labeled GA box and analyzed for the presence of retarded complexes in electrophoretic-mobility-shift assays. In addition to a few constitutive retarded complexes, an inducible GA box-binding activity (GAbf-1) appeared after 5 min, peaked at about 2 h, and was still abundant 12 h after IFN-alpha treatment. In the cytoplasmic fraction GAbf-1 was not detectable before 30 min, continued to increase up to 2 h, but had disappeared within 12 h. GAbf-1 activity was not observed in nuclear extracts treated with IFN-gamma, and was not inhibited by prior treatment with the protein-synthesis inhibitor cycloheximide. When the binding properties of GAbf-1 were compared with those of ISGF-3, the primary transcriptional activator for IFN-alpha-induced genes, a different pattern of retarded complexes was observed. Moreover, as observed by immunoblotting analysis, nuclear extracts from IFN-alpha-treated L1210 cells did not contain the p91/84 subunit of the ISGF3, the best characterized nuclear complex activated by IFN-alpha. Altogether these results indicate that GAbf-1 may be a novel transcription factor exploited by IFN-alpha to activate the 202 inducible gene in murine pre-B leukemia cells.
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PMID:Characterization of nuclear factors involved in 202 gene induction by interferon-alpha in murine leukemia cells. 817 52

The present study investigates the effect of transforming growth factor (TGF)-beta on the production of IL-4 and IFN-gamma by the leukemia Th0 type cell line HUT78, by freshly isolated human T cells, and by antigen specific human T cell clones. We found that IL-4 and IFN-gamma, but not IL-2, production by stimulated HUT78 cells was inhibited by TGF-beta 1. TGF-beta 1 also reduced the accumulation of IL-4 and IFN-gamma specific mRNA in stimulated HUT78 cells. However, IL-2 and IL-7 co-stimulated IL-4 and IFN-gamma production, whereas IL-1, IL-3, IL-5, IL-6, IL-8, tumor necrosis factor-alpha or granulocyte macrophage colony stimulating factor had no effect. Because IL-2 is an important helper cytokine for the production of IL-4 and IFN-gamma, we investigated whether signal transduction through the IL-2 receptor is impaired by TGF-beta 1. We found that tyrosine phosphorylation in response to IL-2 in HUT78 cells was strongly inhibited by a short preincubation with TGF-beta 1. Evidence for an antagonistic role for TGF-beta 1 and IL-2 comes from the finding that high doses of IL-2 could partially overcome TGF-beta 1 mediated inhibition of IL-4 and IFN-gamma production. Similar to its effect on HUT78 cells, TGF-beta 1 also inhibited IL-4 and IFN-gamma production by freshly isolated T cells as well as by human T cell clones. Taken together, our experiments show that the IL-2 dependent cytokines IL-4 and IFN-gamma are both negatively controlled by TGF-beta under conditions where IL-2 production is unaffected by a mechanism which partially involves an inhibition of IL-2/IL-2R signal transduction. These data identify TGF-beta and IL-2 as mutual antagonists in the regulation of IL-4 and IFN-gamma production.
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PMID:Transforming growth factor-beta inhibits IL-4 and IFN-gamma production by stimulated human T cells. 818 98


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