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)

Substance P (SP) is a potent modulator of neuroimmunoregulation. We recently reported that human immune cells express SP and its receptor. We have now investigated the possible role that SP and its receptor plays in HIV infection of human mononuclear phagocytes. SP enhanced HIV replication in human blood-isolated mononuclear phagocytes, whereas the nonpeptide SP antagonist (CP-96,345) potently inhibited HIV infectivity of these cells in a concentration-dependent fashion. CP-96,345 prevented the formation of typical giant syncytia induced by HIV Bal strain replication in these cells. This inhibitory effect of CP-96,345 was because of the antagonism of neurokinin-1 receptor, a primary SP receptor. Both CP-96,345 and anti-SP antibody inhibited SP-enhanced HIV replication in monocyte-derived macrophages (MDM). Among HIV strains tested (both prototype and primary isolates), only the R5 strains (Bal, ADA, BL-6, and CSF-6) that use the CCR5 coreceptor for entry into MDM were significantly inhibited by CP-96,345; in contrast, the X4 strain (UG024), which uses CXCR4 as its coreceptor, was not inhibited. In addition, the M-tropic ADA (CCR5-dependent)-pseudotyped HIV infection of MDM was markedly inhibited by CP-96,345, whereas murine leukemia virus-pseudotyped HIV was not affected, indicating that the major effect of CP-96,345 is regulated by Env-determined early events in HIV infection of MDM. CP-96,345 significantly down-regulated CCR5 expression in MDM at both protein and mRNA levels. Thus, SP-neurokinin-1 receptor interaction may play an important role in the regulation of CCR5 expression in MDM, affecting the R5 HIV strain infection of MDM.
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PMID:Substance P antagonist (CP-96,345) inhibits HIV-1 replication in human mononuclear phagocytes. 1127 18

To address the role of CXCR4 in the cell-surface attachment of the feline immunodeficency virus (FIV), a soluble fusion protein, gp95-Fc, consisting of the surface glycoprotein (SU, gp95) of either a primary (PPR) or cell line-adapted (34TF10) FIV strain was fused in frame with the Fc domain of human immunoglobulin G1. The recombinant SU-immunoadhesins were used as probes to investigate the cellular binding of FIV SU. In agreement with the host cell range properties of both viruses, binding of 34TF10 gp95-Fc was observed for all cell lines tested, whereas PPR gp95-Fc bound only to primary feline T cells. 34TF10 gp95-Fc also bound to Jurkat and HeLa cells, consistent with the ability of FIV to use human CXCR4 as a fusion receptor. As expected, 34TF10 gp95-Fc binding to Jurkat cells was blocked by addition of stromal cell-derived factor 1alpha (SDF-1alpha), as was binding to the 3201 feline lymphoma cell line. However, SDF-1alpha, RANTES, macrophage inflammatory protein 1beta, and heparin all failed to inhibit the binding of either gp95-Fc to primary T cells, suggesting that a non-CXCR4 receptor is involved in the binding of FIV SU. In this regard, an unidentified 40-kDa protein species from the surface of primary T cells but not Jurkat and 3201 cells specifically coprecipitated with both gp95-Fc. Yet another type of binding of 34TF10 gp95-Fc to adherent kidney cells was noted. SDF-1alpha failed to block the binding of 34TF10 gp95-Fc to either HeLa, Crandel feline leukemia, or G355-5 cells. However, binding was severely impaired in the presence of soluble heparin, as well as after enzymatic removal of surface heparans or on cells deficient in heparan expression. These overall findings suggest that in addition to CXCR4, a non-CXCR4 receptor and cell-surface heparans also play an important role in FIV gp95 cell surface interactions on specific target cells.
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PMID:Binding of recombinant feline immunodeficiency virus surface glycoprotein to feline cells: role of CXCR4, cell-surface heparans, and an unidentified non-CXCR4 receptor. 1131 23

CXCR4 is the major co-receptor used by X4 strains of human immunodeficiency virus type I (HIV-1). In HIV-1-infected patients, the appearance of X4 strains (T cell line-tropic) correlates with disease progression. Since its discovery, the CXCR4 co-receptor has been a major target for different agents which block its function, such as stromal-derived factor 1alpha (SDF-1alpha) and the anti-CXCR4 monoclonal antibody, 12G5. In the present studies, the 12G5 hybridoma was used to construct a single-chain variable antibody fragment (SFv). Murine leukemia virus (MLV) and simian virus 40 (SV(40)) were utilized as delivery vehicles for the anti-CXCR4 SFv. Intracellular expression of the anti-CXCR4 SFv led to down-regulation of this critical co-receptor, as demonstrated by immunostaining. This effect significantly and specifically protected transduced cells from challenge with HIV-1, as measured by HIV-1 p24 antigen expression. Inhibition of HIV-1 replication was specific for X4 HIV-1 strains as demonstrated by MAGI assays. HeLa-CD4/betagal-CCR5 cells expressing the anti-CXCR4 SFv showed significant inhibition of infectivity by the X4 HIV-1 strain NL4-3, but not with the R5 HIV-1 strain Bal. Thus, this anti-HIV-1 molecular therapy has the potential to inhibit HIV-1 replication and virion spread. Targeting CXCR4 by intracellular immunization could be of additional benefit to certain HIV-1-infected patients on highly active antiretroviral therapy (HAART).
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PMID:Inhibition of HIV-1 infection by down-regulation of the CXCR4 co-receptor using an intracellular single chain variable fragment against CXCR4. 1131 18

Chemokines are a family of 8-10 kDa proteins with a wide range of biological activities including the regulation of leukocyte trafficking, modulation of haemopoietic cell proliferation and adhesion to extracellular matrix molecules. Using a panel of chemokine receptor-specific monoclonal antibodies (MoAb) in a multicolour flow cytometry approach we analysed the expression of the lymphocyte-associated chemokine receptors CXCR4, CXCR5, CCR5 and CCR6 in B cell acute lymphoblastic leukaemia (precursor B-ALL; six cases), B cell chronic lymphocytic leukaemia (B-CLL; 31 cases), multiple myeloma (10 cases), mantle cell lymphoma (MCL, four cases), follicular lymphoma (FL, three cases) and hairy cell leukaemia (HCL, five cases). We demonstrate that CXCR4, CXCR5 and CCR6 are differentially expressed in these B lymphoproliferative disorders depending on the maturational stage of the malignant B cell population investigated. In particular, we found that CXCR4 is strongly expressed on immature ALL blasts whereas no surface immunoreactivity for CXCR5, CCR5 and CCR6 was observed. By contrast, non-Hodgkin's lymphomas (NHLs) corresponding to more mature peripheral B cell subsets (ie B-CLL and MCL) exhibited high expression levels of CXCR4 and CXCR5. Analysis of terminally differentiated myeloma cells revealed a down-regulation of CXCR4, CXCR5 and CCR6. CCR5, which is not expressed in normal B cells, was also absent from the majority of NHLs. However, CCR5 staining was seen in three of five cases of HCL, representing the first example of cross-lineage aberrant chemokine receptor expression in malignant haemopoietic cells.
Leukemia 2001 May
PMID:Differential expression of chemokine receptors in B cell malignancies. 1136 35

OX40 is a member of the tumor necrosis factor (TNF) receptor superfamily and known to be an important costimulatory molecule expressed on activated T cells. To investigate the role of costimulation of OX40 in human immunodeficiency virus type 1 (HIV-1) infection by its natural ligand, gp34, the OX40-transfected ACH-2 cell line, ACH-2/OX40, chronically infected with HIV-1, was cocultured with paraformaldehyde (PFA)-fixed gp34-transfected mouse cell line, SV-T2/gp34. The results showed that HIV-1 production was strongly induced. This was followed by apparent apoptosis, and both processes were specifically inhibited by the gp34-specific neutralizing monoclonal antibody 5A8. Endogenous TNF alpha (TNF-alpha) and TNF-beta production were not involved in the enhanced HIV-1 production. Furthermore, enhanced HIV-1 transcription in gp34-stimulated ACH-2/OX40 cells was dependent on the kappa B site of the HIV-1 long terminal repeat, and the OX40-gp34 interaction activated NF-kappa B consisting of p50 and p65 subunits. When primary activated CD4(+) T cells acutely infected with HIV-1(NL4-3) (CXCR4-using T-cell-line-tropic) were cocultured with PFA-fixed gp34(+) human T-cell leukemia virus type 1-bearing MT-2 cells or SV-T2/gp34 cells, HIV-1 production was also markedly enhanced. The enhancement was again significantly inhibited by 5A8. The present study first shows that OX40-gp34 interaction stimulates HIV-1 expression and suggests that OX40 triggering by gp34 may play an important role in enhancing HIV-1 production in both acutely and latently infected CD4(+) T cells in vivo.
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PMID:OX40 stimulation by gp34/OX40 ligand enhances productive human immunodeficiency virus type 1 infection. 1143 53

The microbicidal activity of sodium lauryl sulfate (SLS) against human immunodeficiency virus type 1 (HIV-1) was studied in cultured cells. Pretreatment of HIV-1(NL4-3) with SLS decreased, in a concentration-dependent manner, its infectivity when using 1G5 as target cells. In the absence of a viral pretreatment period or when 1G5 cells were pretreated with SLS, the surfactant-induced inactivation of viral infectivity was less pronounced, especially at concentrations between 375 and 550 microM. SLS had no effect on HIV-1 when the virus was adsorbed to 1G5 cells by a 2-h incubation period. SLS almost completely inhibited the fusion process by decreasing the attachment of HIV-1 to target cells. SLS also inhibited the infectivity of HIV-1-based luciferase reporter viruses pseudotyped with the amphotropic murine leukemia virus envelope (which enters cells in a CD4-, CCR5-, and CXCR4-independent manner), indicating that SLS may inactivate other envelope viruses. In contrast, no effect was seen with vesicular stomatitis virus envelope glycoprotein G (which enters cells through receptor-mediated endocytosis) pretreated with up to 700 microM SLS. SLS also decreased, in a dose-dependent manner, the HIV-1-dependent syncytium formation between 1G5 and J1.1 cells after a 24-h incubation. The reduction of luciferase activity was more pronounced when J1.1 cells (which express HIV-1 proteins on their surface) were pretreated with SLS rather than 1G5 cells. Taken together, our results suggest that SLS could represent a candidate of choice for use in vaginal microbicides to prevent the sexual transmission of HIV and possibly other pathogens causing sexually transmitted diseases.
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PMID:Sodium lauryl sulfate abrogates human immunodeficiency virus infectivity by affecting viral attachment. 1145 79

The C-X-C chemokine SDF-1 and its receptor CXCR4, mediate a pivotal role in the pathophysiology of HIV-1 infection and vascular inflammatory diseases. In this study, we investigated the pharmacological properties of SDF-1alpha interaction with CXCR4 in human leukemia cell lines. Our data, based on [125I]-SDF-1alpha radioligand binding, SDF-1alpha-induced [35S]-GTPgammaS binding and use of specific CXCR4 antagonist AMD3100 reveals the complex nature of SDF-1alpha-CXCR4 interaction. Firstly, homologous competition with cold SDF-1alpha revealed a bimodal ligand displacement curve and secondly, although AMD3100 inhibited both SDF-1alpha-mediated chemotaxis (IC(50)=4.7 nM) and [35S]-GTPgammaS binding (IC(50)=7.4 nM) with high affinity, it was intriguingly up to 3000-fold less potent (IC(50)=15.2 microM) in the radioligand binding assay. These results provide pharmacological evidence for the recently described two-site model for SDF-1alpha-CXCR4 interaction. Accordingly, inhibition of SDF-1alpha binding to one of the receptor sites is sufficient to antagonize function, without causing its complete displacement from the receptor. Furthermore, these findings have important implications in the development and evaluation of CXCR4-selective small molecule antagonists for therapeutic use.
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PMID:Pharmacological evidence for complex and multiple site interaction of CXCR4 with SDF-1alpha: implications for development of selective CXCR4 antagonists. 1147 Jan 48

AC133 is a novel 5-transmembrane antigen present on a CD34((bright)) subset of human hematopoietic stem cells (HSCs) and it is also expressed on the subset of CD34 positive (CD34(+)) leukemias. But the clinical significance of AC133 expression on leukemic blasts is not yet known. We investigated the expression of AC133 antigen on blast cells of acute leukemia. Forty-one cases of acute leukemia were examined for expression of AC133, CD34, and other antigens using multicolor flow-cytometry. Samples were considered positive if at least 20% of the cells specifically stained with monoclonal antibodies (MoAbs) revealed a higher fluorescence intensity compared to cells of corresponding negative control samples (=20% cut-off level). 14/36 (38.9%) acute myelogenous leukemia (AML) samples and 6/20 (30%) acute lymphoblastic leukemia (ALL) samples were positive for AC133, the difference was not significant. All AC133 positive (AC133(+)) leukemias expressed CD34, whereas 13 of 33 CD34(+) leukemias were negative for AC133, and AC133(+)/CD34(-) leukemia was not found. Expression rates of CD31, CD62L, CD62E, CD105 and CD144 were significantly higher in AC133(+) leukemia compared to those of AC133(-) leukemia (P=0.045, P<0.001, P<0.001, P<0.001, P=0.003, respectively), but bcl-2, CXCR-1, CXCR4, VLA-4, CD106 expression rates were not significantly different between AC133(+) and AC133(-) leukemias. None of the clinical prognostic markers such as age, hemogram, lactate dehydrogenase, and chromosomal aberration were significantly different between AC133(+) and AC133(-) leukemias. CR rates of AC133(+) AML and AC133(-) AML were not significantly different, although there was a trend toward higher CR rates in AC133(-) AML (18/22[81.8%] AC133(-) AML versus 9/14[64.3%] AC133(+) AML), but the 1-year relapse rate of AC133(+) AML was significantly higher than that of AC133(-) AML (8/9 (88.9%) versus 7/19 (36.8%), P=0.016). Median disease-free survival (DFS) times of AC133(+) and AC133(-) AML were significantly different (11 and 18 months, respectively, P=0.006), although overall survival (OS) times were not significantly different (AC133(+) 15 months versus AC133(-) 20 months, respectively, P=0.06). Similar results regarding clinical outcomes were found when AC133(+)/CD34(+) and AC133(-)/CD34(+) were analyzed separately, but the difference did not attain statistical significance. In ALL, 9/11 (81.8%) AC133(-) and 2/4 (50%) AC133(+) cases achieved CR, but the difference was not significant. Four of 11 AC133(-) ALL (36.4%) and 2 of 3 AC133(+) ALL (66.7%) relapsed within 1 year. In survival analysis, median DFS time and OS time of the AC133(+) group were 7 and 18 months, respectively, and these were not significantly different from those of the AC133(-) group (median DFS 15, OS 22 months, respectively). Our results demonstrate that AC133 expression in AML blasts is associated with poor clinical outcomes in terms of higher early relapse and shorter disease-free survival, suggesting that the AC133 antigen might provide the prognostic stratification of acute leukemia. However, to verify the effect of AC133 expression on the therapeutic outcomes of adult acute leukemia, further study including more cases is needed.
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PMID:AC133 antigen as a prognostic factor in acute leukemia. 1148 69

Murine leukemia virus (MuLV) can be pseudotyped with a variant of the human immunodeficency virus (HIV) envelope gene encoding the surface glycoprotein gp120-SU and a carboxy-terminally truncated transmembrane (TM) protein with only seven cytoplasmic amino acids. MuLV/HIV-1 pseudotyped retroviral vectors selectively target gene transfer to human cells expressing both CD4 and CXCR4. To apply this vector system to gene therapy of human diseases, we generated a stable packaging cell line, FLY-HIV-87, expressing the MuLV gag and pol genes and the C-terminally truncated variant of the HIV-1 envelope gene, but no retroviral vector genome. Production of infectious vector particles was tested after the introduction of different vector genomes and was in the range of 5x10(5) IU/ml. The vector particles could be concentrated up to 25-fold. Specific and efficient gene transfer into CD4/CXCR4 expressing cell lines and stimulated primary human CD4+ peripheral blood lymphocytes was achieved. Thus the packaging cell line FLY-HIV-87 is highly suitable for gene therapy of disorders of human T-helper cells.
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PMID:A packaging cell line generating CD4-specific retroviral vectors for efficient gene transfer into primary human T-helper lymphocytes. 1154 19

Childhood acute lymphoblastic leukaemia (ALL) is a malignancy with the potential to infiltrate the liver, spleen, lymph nodes and brain. Such extramedullary presentation is important for understanding the biology of childhood ALL and also for developing new prognostic parameters. A potential mechanism in the trafficking of leukaemia cells is the interaction of the chemokine receptor CXCR4, which is expressed on ALL cells, and its ligand stromal cell-derived factor-1 (SDF-1), produced by stromal cells in bone marrow and extramedullary organs. Functionality of CXCR4 was demonstrated by a high correlation between cell surface density of CXCR4 and transendothelial migration of leukaemia blasts towards a gradient of SDF-1 (r = 0.73, P = 0.001). Inhibition of SDF-1-induced migration by an anti-CXCR4 monoclonal antibody (78.33 +/- 23.86% inhibition) evidenced the specificity of CXCR4 to SDF-1. In order to evaluate clinical significance of CXCR4 expression, lymphoblasts from the bone marrow of 73 patients with and without extramedullary organ infiltration were compared. Multiparameter flow cytometry revealed that lymphoblasts from patients with high extramedullary organ infiltration, defined as ultrasonographically measured enlargement of liver or spleen, expressed the CXCR4 receptor at higher fluorescence intensity (median 66.12 +/- 66.17) than patients without extramedullary organ infiltration (median 17.56 +/- 19.29; P < 0.001). Consequently, high expression of CXCR4 was strongly predictive for extramedullary organ involvement, independently of the peripheral lymphoblast count. Highest CXCR4 expression was seen in mature B ALL (median 102.74 +/- 92.13; P < 0.003), a disease characterized by a high incidence of extramedullary bulky disease. As high expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood ALL, we suggest that CXCR4 and its ligand play an essential role in extramedullary invasion.
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PMID:High expression of the chemokine receptor CXCR4 predicts extramedullary organ infiltration in childhood acute lymphoblastic leukaemia. 1240 8


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