Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
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

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.
 ...
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
 ...
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.
 ...
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

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.
 ...
PMID:Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox. 1214 23

DAB(389)IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB(389)IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical trials of patients whose tumor cells express a component of the IL-2R, the response rates were 18% for B-cell non-Hodgkin lymphoma (NHL) and 30% for cutaneous T-cell lymphoma (CTCL). In this study, we examined the effects of arginine butyrate on IL-2R expression and susceptibility of leukemia cells to intoxication by DAB(389)IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rbeta) is upregulated in the presence of low concentrations of arginine butyrate (0.06mM) which had no direct growth inhibitory effect on the cells. To explore mechanisms of this upregulation, we examined the effect of 0.06mM arginine butyrate on relevant transcriptional elements and on histone deacetylase and found activation of cAMP response element (CRE) but not NFAT or NFKB, as well as inhibition of histone deacetylase (HDAC). Our results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL-2R expressing leukemia cells to DAB(389)IL-2.
 ...
PMID:Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene. 1244 77

Human immunodeficiency virus type 1 (HIV-1), feline immunodeficiency virus (FIV), and Moloney murine leukemia virus (MoMLV) integrases were stably expressed to determine their intracellular trafficking. Each lentiviral integrase localized to cell nuclei in close association with chromatin while the murine oncoretroviral integrase was cytoplasmic. Fusions of pyruvate kinase to the lentiviral integrases did not reveal transferable nuclear localization signals. The intracellular trafficking of each was determined instead by the transcriptional coactivator LEDGF/p75, which was required for nuclear localization. Stable small interfering RNA expression eliminated detectable LEDGF/p75 expression and caused dramatic, stable redistribution of each lentiviral integrase from nucleus to cytoplasm while the distribution of MoMLV integrase was unaffected. In addition, endogenous LEDGF/p75 coimmunoprecipitated specifically with each lentiviral integrase. In vitro integration assays with preintegration complexes (PICs) showed that endogenous LEDGF/p75 is a component of functional HIV-1 and FIV PICs. However, HIV-1 and FIV infection and replication in LEDGF/p75-deficient cells was equivalent to that in control cells, whether cells were dividing or growth arrested. Two-long terminal repeat circle accumulation in nondividing cell nuclei was also equivalent to that of LEDGF/p75 wild-type cells. Virions produced in LEDGF/p75-deficient cells had normal infectivity. We conclude that LEDGF/p75 fully accounts for cellular trafficking of diverse lentiviral, but not oncoretroviral, integrases and is the main lentiviral integrase-to-chromatin tethering factor. While lentiviral PIC nuclear import is unaffected by LEDGF/p75 knockdown, this protein is a component of functional lentiviral PICs. A role in HIV-1 integration site distribution merits investigation.
 ...
PMID:LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. 1530 44

We have previously shown that the p75 isoform of the transcriptional co-activator lens epithelium-derived growth factor (LEDGF) interacts tightly with human immunodeficiency virus (HIV)-1 integrase (IN) and is essential for nuclear targeting of this protein in human cells (Cherepanov, P., Maertens, G., Proost, P., Devreese, B., Van Beeumen, J., Engelborghs, Y., De Clercq, E., and Debyser, Z. (2003) J. Biol. Chem. 278, 372-381; Maertens, G., Cherepanov, P., Pluymers, W., Busschots, K., De Clercq, E., Debyser, Z., and Engelborghs, Y. (2003) J. Biol. Chem. 278, 33528-33539). Here the interaction between recombinant LEDGF/p75 and HIV-1 IN was examined in a pull-down binding test. LEDGF/p75 was shown to increase the solubility of HIV-1 IN. Next, fluorescent correlation spectroscopy was used to measure the interaction of LEDGF/p75 or the complex of HIV-1 IN and LEDGF/p75 with a specific double-stranded DNA oligonucleotide. Whereas LEDGF/p75 displayed only a moderate affinity for DNA, it strongly promoted the binding of HIV-1 IN to DNA. This effect was specific for the p75 isoform of LEDGF and was not seen with p52. In the pull-down assay LEDGF/p75 interacted with HIV-1, HIV-2, and feline immunodeficiency virus IN, but not with the IN of human T-cell lymphotropic virus type 2, Moloney murine leukemia virus, or Rous sarcoma virus. These results strongly suggest that the interaction of LEDGF/p75 with IN is specific to lentiviridae. LEDGF/p75 stimulated the binding of HIV-1 and HIV-2 IN, but not Moloney murine leukemia virus or Rous sarcoma virus IN, to an aspecific DNA. These results provide supporting evidence for our hypothesis that LEDGF/p75 plays a role in the tethering of lentiviral IN to the chromosomal DNA.
 ...
PMID:The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. 1574 13


<< Previous 1 2 3 4 5 Next >>