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)

Matrix metalloproteinases have been reported to be involved in tumor cell invasion and metastasis. Dissemination of malignant cells in acute myeloid leukemia (AML) may be mediated by similar mechanisms. Here, we report, that the t(15/17)+ acute promyelocytic leukemia (APL) cell line NB4 constitutively expresses and releases the proenzyme form of matrix metalloproteinase-9 (MMP-9, 92 kDa type IV collagenase/gelatinase, gelatinase B), as well as tissue inhibitor of metalloproteinases-1 (TIMP-1). Both proteins were identified by N-terminal amino acid sequence analysis after purification using gelatin Sepharose affinity chromatography. Whereas 12-O-tetradecanoylphorbol-13 acetate (TPA) increased both MMP-9 and TIMP-1 mRNA levels, tumor necrosis factor-alpha (TNF-alpha) stimulated only MMP-9 gene expression in a dose- and time-dependent manner. Neutralizing monoclonal antibodies (MoABs) to TNF-alpha (anti-TNF-alpha) decreased the constitutive and TPA-dependent expression of MMP-9 but did not influence TIMP-1 expression, either in unstimulated or in TPA-treated NB4 cells. FACS analyses showed that NB4 cells express both TNF receptor 1 (TNF-R1) and TNF-R2 to a similar extent. Blocking MoABs against TNF-R 1 (anti-TNF-R1) decreased the constitutive expression of MMP-9, whereas anti-TNF-R2 had almost no effect. Our results show, that in NB4 cells the expression of MMP-9 but not of TIMP-1 is maintained by autocrine stimulation with TNF-alpha. Thus, leukemic cells may be enabled to leave the bone marrow and infiltrate peripheral tissues by a dysfunction in the regulation of the MMP-9:TIMP-1 equilibrium, possibly triggered through autostimulation by TNF-alpha.
Leukemia 1998 Jul
PMID:Autocrine regulation of matrix metalloproteinase-9 gene expression and secretion by tumor necrosis factor-alpha (TNF-alpha) in NB4 leukemic cells: specific involvement of TNF receptor type 1. 966 1

The leader signal sequence of the non-structural gag-encoded glycoprotein precursor, Pr75gag, of Friend murine leukemia virus (F-MuLV) contains overlapping epitopes, SIVLCCLCL (p71-79) and CCLCLTVFL (p75 83) that activate Friend virus (FV)-induced tumor (FBL-3)-specific cytotoxic T-lymphocytes (CTL) (Kondo et al., J. Virol., 69, 1995, 6735-6741; Chen et al., J. Virol., 70, 1996, 7773-7782). It was investigated whether these two peptides are recognized by a single CTL clone or by individual clones with different specificities. The results show that both hydrophobic and cysteine-containing peptides are bound to H-2Db class I major histocompatibility complex (MHC) molecules and cross-recognized by a single CTL clone as well as bulk-cultured CTL from the spleens of mice immunized with FBL-3. The peptide p71-79 was effective for sensitizing target cells to lysis by CTL in the concentration of common antigenic peptides. Moreover, peptide p75-83 was 1000-fold more potent than the peptide p71-79. Specific cytotoxicity assays with variant peptides with alanine- and serine-substitutions suggested a highly complex function of the disulfide bond-forming peptides potentially sensitive to small sequence differences. The dominance of CTL responses to the transmembrane region is discussed in light of the high affinity of a novel hydrophobic peptide to compete with other peptides for binding to MHC molecules.
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PMID:Overlapping epitopes of friend murine leukemia virus gag-encoded leader sequence recognized by single cytotoxic T-lymphocyte clones. 967 45

Sensory neurons isolated from dorsal root ganglia of postnatal mice were analysed for cell surface p75, using fluorescent antibody staining with flow cytometry. They were found to follow a single bell-shaped distribution of p75 level, with no discrete group of p75-negative neurons. Sensory neurons were then separated by fluorescence-activated cell sorting into high- and low-p75 populations, consisting of cells within the highest and lowest 15th percentiles, respectively, of p75 expression levels. The sorted neurons were tested for trkA staining. All high-p75 neurons were positive for trkA, while many low-p75 cells were negative for trkA. The sorted neurons were placed in culture, and their survival in the absence and presence of various neurotrophins was measured. Low-p75 cells were found to have enhanced survival in the absence of neurotrophins, while cells with high p75 levels had reduced survival, compared to the overall population. Almost all high-p75 neurons were rescued with nerve growth factor, whereas less than half of the low-p75 cells were rescued. The slope of the dose response to nerve growth factor did not differ markedly between high- and low-p75 cells. High-p75, but not low-p75, neurons were responsive to neurotrophin-3. There was only a small response to either brain-derived neurotrophic factor or neurotrophin-4 in both high- and low-p75 neurons. All low-p75 neurons, and 68% of high-p75 neurons, survived in the presence of ciliary neurotrophic factor. These results, while consistent with our hypothesis that p75 may act as a death factor in postnatal sensory neurons, also imply a role for p75 in the modulation of trk responsiveness to neurotrophins. They also indicate overlapping neurotrophin responses in sensory neurons, especially in those with high p75 levels. A large proportion of low-p75 cells were not responsive to any of the nerve growth factor-related neurotrophins, suggesting an important role for cytokines such as ciliary neurotrophic factor and leukaemia inhibitor factor in the survival of sensory neurons.
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PMID:Rescue of dorsal root sensory neurons by nerve growth factor and neurotrophin-3, but not brain-derived neurotrophic factor or neurotrophin-4, is dependent on the level of the p75 neurotrophin receptor. 968 65

The tumour necrosis factor (TNF)/TNF-receptor (TNFR) complex plays a role in the growth of leukaemic cells. We retrospectively investigated the relationship between pretreatment serum concentration of soluble TNFR (p55- and p75-sTNFRs) and outcome in adult acute myeloid (AML 82 cases) and lymphoid (ALL 44 cases) leukaemia. Both sTNFRs were significantly higher in AML (p55-sTNFR 4.53 +/- 3.7, median 3.75; p75-sTNFR 6.51 +/- 5.25 ng/ml, median 4.72) and ALL sera (3.31 +/- 1.5, median 2.95; 5.30 +/- 2.3 ng/ml, median 4.56, respectively) than in controls (1.89 +/- 0.5, median 1.98; 2.22 +/- 0.8 ng/ml, median 2.37) (P < 0.01 for both sTNFRs). Fresh leukaemic cells expressed p55- and p75-sTNFRs, which were modulated and released into the supernatant (SN) following short-term in vitro culture, suggesting that in vivo sTNFRs were also leukaemia-derived. Whereas no correlation was observed between sTNFRs and outcome in ALL, in AML higher p55-sTNFR levels (> 3.75 ng/ml) were associated with shorter disease-free survival (DFS) (P = 0.006) and overall survival (OS) (P = 0.0004). At multivariate analysis p55-sTNFR was the most significant predictor of DFS (P = 0.006) and OS (P < 0.001). Our data suggest that the prognostic significance of p55-sTNFR in AML could be related to relevant biological features of AML blasts.
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PMID:Serum levels of p55 and p75 soluble TNF receptors in adult acute leukaemia at diagnosis: correlation with clinical and biological features and outcome. 973 54

We have studied the expression of cytokine receptors CD25 (IL-2Ra,55kD), CD116 (hGM-CSRF,145kD), CD117 (CSFR,145kD), CD120a (TNFR,55kD), CD120b (TNFR,75kD), CD121a (IL-1R, type I, 80kD), CD123 (IL-3R), CD124 (IL-4R, 140kD), CD126 (IL-6R, 80kD), CDw127 (IL-7R, 75kD), CDw128 (IL-8R), CD130 (gp130 subunit), CD131 (common beta), CD134 (OX40) and also CD95 (Fas antigen) on the myeloid leukemic cells. Cells from peripheral blood or bone marrow of 30 patients with disorders in myeloid lineage included mostly acute myeloid leukemias (with high leukocyte count and percentage of blasts) were analyzed for the expression of surface membrane molecules by indirect immunofluorescence method evaluated by flow cytometry. The findings indicate that some monoclonal antibodies have a reactivity against cytokine receptors of pathological cells in individual cases, but with very variable qualitative and quantitative (number copies/cell) expression (preliminary results). The leukemic cells demonstrate unique cytokine receptor profiles, which reveal the great diversity of immunophenotypes within the main functional characterization of blood malignancies. The immunophenotype heterogeneity of leukemic cells has proved to be much greater than to match with existing classification criteria. This fact could raise the necessity of further evaluation and specification of cytokine markers of the myeloid acute leukemias. On the other hand, detection of cytokine receptors on the leukemia cells is important for cytokine therapy.
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PMID:Expression of cytokine receptors on different myeloid leukemic cells. 989 Jun 61

Serum lactic dehydrogenase (LDH) is an important prognostic factor in patients with non-Hodgkin's lymphoma (NHL). We have examined the LDH isoenzyme content in serum and CSF of patients with NHL, at diagnosis and at relapse. In patients with increased serum LDH at diagnosis, the percentage of isoenzyme 2 was increased in 52% of patients and the absolute value of isoenzyme 3 was increased in 64% of patients. In relapsing patients these values were respectively 69% and 65%. Conversely in patients with increased serum LDH due to myeloid regeneration after chemotherapy, isoenzymes 4 and 5, but not isoenzymes 2 or 3, were increased. High absolute values of isoenzyme 3 were correlated with an altered performance status, advanced tumor stage, and aggressive histology whereas high isoenzyme 2 percentages were correlated with altered performance status only. Among patients with high total serum LDH, a high content of isoenzyme 2 and a high absolute value of isoenzyme 3 were correlated with high serum levels of TNFalpha and TNF receptor p75. Analysis of total LDH and LDH isoenzyme profiles in CSF did not reveal any correlation with meningeal involvement by lymphoma. High isoenzyme 2 percentages and high absolute values of isoenzyme 3 in serum were both significantly associated with a shorter freedom-from-progression and overall survival. Isoenzyme 3 remained a prognostic factor for survival even when considering only patients with high total serum LDH at diagnosis. We conclude that there are some characteristic serum LDH isoenzyme profiles in patients with NHL and that some of these specific alterations may help refine the prognostic value of total serum LDH.
Leukemia 1999 May
PMID:Profiles and prognostic values of LDH isoenzymes in patients with non-Hodgkin's lymphoma. 1037 88

The HTLV-I provirus-encoded Tax protein induces NF-kappaB in Tax-transfected Jurkat T cells or HTLVL-I- infected T cells in vitro. Tax induction of NF-kappaB is presumed to be involved in proliferation and activation of primary leukemia cells in vivo. Recent studies have demonstrated that NF-kappaB activities in human T cells are mediated by at least four c-Rel-related DNA binding proteins - p50, p55, p75 and p85. We examined the significance of NF-kappaB induction in primary adult T cell leukemia cells and the induction kinetics of each of the four NF-kappaB species. Marked NF-kappaB activity was detected using an electrophoretic mobility shift assay (EMSA) in the primary cells of patients with acute disease, but little activity was noted in the cells of chronic patients. NF-kappaB activity was enhanced in a time-dependent manner in acute type cells cultured with mitogen-free medium; there was no induction of activity in chronic type cells. UV crosslinking demonstrated all four species of NFkappaB complex - high levels of p50 and lower levels of p55 and p75, in acute type cells; chronic type cells showed only the p50. As a control, normal resting T cells similarly showed only p50; control cells showed little change in activity when cultured without mitogenic stimulation, analogous to chronic type ATL. Northern blotting revealed enhancement of c-rel (encoding p85) and KBFI (encoding p50 and p55) expression in acute type cells during culture, while there was no significant enhancement of mRNAs in chronic type ATL cells or unstimulated normal T cells. Northern blotting also revealed that Tax is upregulated at the mRNA level in acute- but not chronic-type cells during culture. Expression of c-rel and KBF1 mRNAs in acute type cells appeared to be related to Tax mRNA expression. These results suggest that Tax is capable of inducing nuclear expression of all four NF-kappaB species in primary ATL cells of acute type patients, with marked effects on p55, p75, and p85. Tax induction of NF-kappaB species is regulated, at least in part, at a pretranslational level involving increases in c-rel and KBF1 mRNA.
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PMID:NF-kappaB involvement in the activation of primary adult T-cell leukemia cells and its clinical implications. 1039 Jan 92

We used the human myelomonoblastic leukemia cell line PLB-985 to study the effects of temperatures ranging from 37 degrees C to 43 degrees C for 1 h on the induction of apoptosis and cell cycle distribution in leukemia cells. The threshold temperature for the onset of apoptosis was 42 degrees C. Whereas hyperthermia exerted no effect on the expression of Bcl-2 and Bax, heat induced a >30-fold increase of tumor necrosis factor (TNF) alpha mRNA expression and a significant increase in TNF-alpha protein secretion. This endogenous production of TNF-alpha correlated directly with the temperature-induced apoptode effect. Blocking TNF-alpha expression via treatment with pyrrolidinedithiocarbamate or blocking TNF-alpha activity with neutralizing antibodies abrogated heat-provoked apoptosis. In addition, exposure of cell culture supernatant of heat-treated PLB-985 cells to untreated cells induced an apoptotic effect. These data indicate a TNF-a-mediated self eradication of the leukemia cells after heat exposure. Inducing apoptosis with wild-type TNF-alpha or p55 and p75 protein muteins demonstrated that this effect was mediated by the p55 receptor. Interestingly, the autocrine suicidal loop found in immature leukemia cells was lost after granulocytic differentiation with 0.5% N,N-dimethylformamide. These data should be of critical importance for the understanding of the biological impact of fever as well as for developing therapeutic approaches to malignant diseases
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PMID:Role of tumor necrosis factor alpha in hyperthermia-induced apoptosis of human leukemia cells. 1041 2

A 46-year-old woman with a previous diagnosis of sarcoidosis presented with morphologically typical large granular lymphocyte (LGL) leukemia/lymphoma with an aggressive clinical course. Epstein-Barr virus DNA was detected in peripheral blood mononuclear cells by PCR. The phenotype was typical of the T cell lineage (CD2+ CD3+ CD5+ CD7+ CD8+ TCRalphabeta+) but with the absence of the CD16, CD56, CD57 NK cell markers. In addition, the LGLs expressed CD122 (p75) in the absence of CD25 which is characteristic of LGLs. These leukemic LGLs did not exhibit NK activity. The clonal nature of this proliferation was demonstrated by the rearrangement of the TCRgamma gene. This phenotypically unusual but morphologically typical LGL leukemia/lymphoma may represent the clonal expansion of a minor normal subset of T-LGLs which do not express any NK cell markers, probably corresponding to in vivo activated T cells.
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PMID:Aggressive variant of morphologically typical T large granular lymphocyte leukemia/lymphoma lacking NK cell markers. 1115 85

ML-1 human myeloblastic leukemia cells, suspended in serum-depleted medium, proliferate when the insulin-like growth factor-1 (IGF-1) and transferrin (Tf) are supplied, but differentiate to monocytes when these factors are replaced by the tumor necrosis factor-alpha (TNF-alpha). Induction of differentiation, but not of proliferation, involved the selective activation of diverse members of the NF-kappaB family of proteins. In differentiation-induced cells, NF-kappaB (p65) was translocated from the cytoplasm to the nucleus, whereas NF-kappaB (p75) remained localized to the cytoplasm. In contrast, NF-kappaB (p52) was present in the nuclei of proliferation- as well as of differentiation-induced ML-1 cells. The differentiation-specific translocation of NF-kappaB (p65) from the cytoplasm to the nucleus was mediated by an increase in the level of NIK, the NF-kappaB-inducing kinase which, through phosphorylation of IkappaB kinase alpha (Ikappakalpha), causes a decrease in the level of IkappaBalpha, allowing p65 to move from the cytoplasm to the nucleus. The p52/p65 heterodimer formed in the nucleus, bound specifically to the promoter of the tumor suppressor protein p53, effecting a 25 to 30-fold increase in the level of this protein. As we reported previously (Li et al, Cancer Res 1998; 58: 4282-4287), that increase led to the decreased expression of proliferating cell nuclear antigen (PCNA) and to the loss of proliferation-associated DNA synthesis. The ensuing uncoupling of growth from differentiation was followed by the initiation of the monocyte-specific differentiation program.
Leukemia 2001 May
PMID:NF-kappaB (p65/RelA) as a regulator of TNFalpha-mediated ML-1 cell differentiation. 1136 42


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