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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Natural killer (NK) cell-type lymphoproliferative diseases of granular lymphocytes can be subdivided into aggressive NK cell leukemia (ANKL) and chronic NK cell lymphocytosis (CNKL). One reason for the poor outcome in ANKL is leukemic infiltration into multiple organs. The mechanisms of cell trafficking associated with the chemokine system have been investigated in NK cells. To clarify the mechanism of systemic migration of leukemic NK cells, we enrolled nine ANKL and six CNKL cases, and analyzed the expression profiles and functions of chemokine receptors by flowcytometry and chemotaxis assay. CXCR1 was detected on NK cells in all groups, and CCR5 was positive in all ANKL cells. Proliferating NK cells were simultaneously positive for CXCR1 and CCR5 in all ANKL patients examined, and NK cells with this phenotype did not expand in CNKL patients or healthy donors. ANKL cells showed enhanced chemotaxis toward the ligands of these receptors. These results indicated that the chemokine system might play an important role in the pathophysiology of ANKL and that chemokine receptor profiling might be a novel tool for discriminating ANKL cells from benign NK cells.
Leukemia 2005 Jul
PMID:Significance of chemokine receptor expression in aggressive NK cell leukemia. 1590

The human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins (Envs) function as a trimer, mediating virus entry by promoting the fusion of the viral and target cell membranes. HIV-1 Env trimers induce membrane fusion through a pH-independent pathway driven by the interaction between an Env trimer and its cellular receptors, CD4 and CCR5/CXCR4. We studied viruses with mixed heterotrimers of wild-type and dominant-negative Envs to determine the number (T) of Env trimers required for HIV-1 entry. To our surprise, we found that a single Env trimer is capable of supporting HIV-1 entry; i.e., T = 1. A similar approach was applied to investigate the entry stoichiometry of envelope glycoproteins from amphotropic murine leukemia virus (A-MLV), avian sarcoma/leukosis virus type A (ASLV-A), and influenza A virus. When pseudotyped on HIV-1 virions, the A-MLV and ASLV-A Envs also exhibit a T = 1 entry stoichiometry. In contrast, eight to nine influenza A virus hemagglutinin trimers function cooperatively to achieve membrane fusion and virus entry, using a pH-dependent pathway. The different entry requirements for cooperativity among Env trimers for retroviruses and influenza A virus may influence viral strategies for replication and evasion of the immune system.
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PMID:Stoichiometry of envelope glycoprotein trimers in the entry of human immunodeficiency virus type 1. 1616 Jan 41

Truncation of the human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV) gp41 cytoplasmic tail (CT) can modulate the fusogenicity of the envelope glycoprotein (Env) on infected cells and virions. However, the CT domains involved and the underlying mechanism responsible for this "inside-out" regulation of Env function are unknown. HIV and SIV CTs are remarkably long and contain amphipathic alpha-helical domains (LLP1, LLP2, and LLP3) that likely interact with cellular membranes. Using a cell-cell fusion assay and a panel of HIV Envs with stop codons at various positions in the CT, we show that truncations of gp41 proximal to the most N-terminal alpha helix, LLP2, increase fusion efficiency and expose CD4-induced epitopes in the Env ectodomain. These effects were not seen with a truncation distal to this domain and before LLP1. Using a dye transfer assay to quantitate fusion kinetics, we found that these truncations produced a two- to fourfold increase in the rate of fusion. These results were observed for X4-, R5-, and dual-tropic Envs on CXCR4- and CCR5-expressing target cells and could not be explained by differences in Env surface expression. These findings suggest that distal to the membrane-spanning domain, an interaction of the gp41 LLP2 domain with the cell membrane restricts Env fusogenicity during Env processing. As with murine leukemia viruses, where cleavage of a membrane-interactive R peptide at the C terminus is required for Env to become fusogenic, this restriction of Env function may serve to protect virus-producing cells from the membrane-disruptive effects of the Env ectodomain.
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PMID:Regulation of human immunodeficiency virus type 1 envelope glycoprotein fusion by a membrane-interactive domain in the gp41 cytoplasmic tail. 1616 Jan 49

The coreceptor usage of HIV-1 envelope proteins (Env) is mainly dependent on a defined variable region within the V3-loop of Env. Thus, retroviral vectors derived from murine leukemia virus (MLV), which have been pseudotyped with HIV-1 envelope proteins holding different V3-loops, enable selective gene delivery into either CXCR4 or CCR5 positive cultured cells. Here, we tested the distribution of CD4/CCR5-tropic [MLV(HIV)]-pseudotype vectors in transgenic mice expressing CD4 and either CXCR4 or CCR5 of human origin. The specificity of gene transfer was analyzed by ex vivo transduction of spleen cells as well as after i.v. or i.p. injection of transgenic mice. Expression of the transferred marker gene EGFP and vector sequences could be detected exclusively in lymphocytes expressing (hu)CD4 and (hu)CCR5, whereas MLV vectors pseudotyped with the VSV-G envelope glycoprotein mediated gene transfer in mice of all genotypes investigated. These data demonstrated that cell-specific gene delivery via [MLV(HIV)]-pseudotyped vectors, as previously shown for cultured cells, is also achievable in vivo.
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PMID:Selective gene transfer to T lymphocytes using coreceptor-specific [MLV(HIV)] pseudotype vectors in a transgenic mouse model. 1665 Aug 81

There has been increasing interest in the identification of novel HIV entry inhibitors. For the discovery of these entry inhibitors, robust surrogate anti-HIV assays are highly desired. The authors report a novel anti-HIV assay system using Moloney murine leukemia viruses (MMLVs) pseudotyped with cytoplasmic tail-truncated HIV envelope protein gp140. These pseudotyped MMLV-HIVgp140 viral particles carry luciferase transcripts; therefore, robust luciferase signal can be detected in cells infected by these pseudotypes. Polycationic agent polybrene and spinoculation markedly enhanced the infection efficiency of these pseudotypes. It was demonstrated that the tropism of these pseudotypes is dependent on the pseudotyped HIV envelope proteins. MMLV viruses pseudotyped with gp140 from an R5 HIV virus specifically infect CCR5-expressing cells, and viruses pseudotyped with gp140 from an X4 HIV virus specifically infect CXCR4-expressing cells. Furthermore, CCR5 antagonists inhibited only MMLV-gp140(R5) infections, and CXCR4 antagonists inhibited only MMLV-gp140(X4) infections. A variety of known HIV entry inhibitors were tested in both R5- and X4-dependent pseudotype antiviral assays, and the IC50 values generated were consistent with published results. The pseudotype antiviral assay was also used in the characterization of hundreds of novel CCR5 antagonists. The IC50 values determined in this assay were compared with those determined in HIV antiviral and cell-cell fusion (CCF) assays, and good correlation was found between pseudotype antiviral assay and HIV antiviral assay (R2 = 0.9) or CCF assay (R2 = 0.8).
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PMID:Development of a Moloney murine leukemia virus-based pseudotype anti-HIV assay suitable for accurate and rapid evaluation of HIV entry inhibitors. 1684 67

CXCL8 (interleukin-8) interacts with two receptors, CXCR1 and CXCR2, to activate leukocytes. Upon activation, CXCR2 internalizes very rapidly relative to CXCR1 ( approximately 90% versus approximately 10% after 5 min). The C termini of the receptors have been shown to be necessary for internalization but are not sufficient to explain the distinct kinetics of down-regulation. To determine the structural determinant(s) that modulate receptor internalization, various chimeric and point mutant receptors were generated by progressively exchanging specific domains or amino acids between CXCR1 and CXCR2. The receptors were stably expressed in rat basophilic leukemia 2H3 cells and characterized for receptor binding, intracellular Ca(2+) mobilization, phosphoinositide hydrolysis, phosphorylation, internalization, and MAPK activation. The data herein indicate that the second extracellular loop (2ECL) of the receptors is critical for the distinct rate of internalization. Replacing the 2ECL of CXCR2 with that of CXCR1 (B(2ECL)A) or Asp(199) with its CXCR1 valine counterpart (B(D199V)A) delayed CXCR2 internalization similarly to CXCR1. Replacing Asp(199) with Asn (B(D199N)) restored CXCR2 rapid internalization. Structure modeling of the 2ECL of the receptors also suggested that Asp(199) plays a critical role in stabilizing and modulating CXCR2 rapid internalization relative to CXCR1. B(D199N) internalized rapidly but migrated as a single phosphorylated form like CXCR1 ( approximately 75 kDa), whereas B(2ECL)A and B(D199V)A showed slow and fast migrating forms like CXCR2 ( approximately 45 and approximately 65 kDa, respectively) but internalized like CXCR1. These data further undermine the role of receptor oligomerization in CXCL8 receptor internalization. Like CXCR1, B(D199V)A also induced sustained ERK activation and cross-desensitized Ca(2+) mobilization to CCR5 relative to B(D199N) and CXCR2. Altogether, the data suggest that the 2ECL of the CXCL8 receptors is important in modulating their distinct rate of down-regulation and thereby signal length and post-internalization activities.
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PMID:CXCR1 and CXCR2 activation and regulation. Role of aspartate 199 of the second extracellular loop of CXCR2 in CXCL8-mediated rapid receptor internalization. 1720 68

Leukemia inhibitor factor (LIF) has been shown to potently inhibit HIV-1 replication in vitro and in human organ explant cultures. Furthermore, LIF activates the Jak/Stat signaling pathway with which many viruses, including HIV-1, interfere. We used CXCR4 and the LIF signaling receptor (gp130)-expressing cMAGI cells transfected with CD4, CCR5, and HIV-LTR-beta-galactosidase as a model system to investigate the potential involvement of Stat proteins in the anti-HIV-1 effect of LIF. Pretreatment with recombinant human (rh)LIF resulted in a significantly reduced uptake of HIV-1(BaL) , HIV-1(LAI), and SIVmac251 viral particles without affecting uptake of murine leukemia retroviral particles. HIV-1(BaL), HIV-1(LAI), as well as rhLIF selectively induced phosphorylation of Stat 3 but not Stat 1 or Stat 5. However, treatment of cMAGI cells with rhLIF prior to HIV-1 infection downregulated the HIV-1-mediated Stat 3 phosphorylation. In addition, peripheral blood mononuclear cells (PBMCs) transfected with Stat 3 siRNA prior to HIV-1(LAI) or HIV-1(BaL) infection produced significantly less HIV-1 p24 antigen as compared to nontransfected HIV-1(LAI) and HIV-1(BaL)-infected PBMCs. Thus, the Jak/Stat signaling pathway is important for the HIV-1 replication life cycle and rhLIF excerts its anti-HIV-1 activity by disrupting this signaling cascade.
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PMID:Leukemia inhibitor factor (LIF) inhibits HIV-1 replication via restriction of stat 3 activation. 1741 73

T-cell large granular lymphocyte (T-LGL) leukemia and chronic natural killer (NK) cell lymphocytosis (CNKL) are major subtypes of lymphoproliferative disease of granular lymphocytes (LDGL). To clarify the mechanism of LGL proliferation and the relationship with the chemokine system in LDGL, we enrolled 22 T-LGL leukemia patients and 8 CNKL cases, analyzed the expression profiles of chemokine receptors, and measured the serum concentrations of the corresponding chemokines. There were no significant differences in chemokine receptor expression profiles between T-LGL leukemia patients and healthy donors. An association of CCR5 and CXCR3 expression levels on LGLs was recognized in T-LGL leukemia patients (r = 0.84; P < .001). Among the chemokines, serum IP-10 and MIG levels were significantly higher in LDGL patients than in healthy donors (P < .05, and P < .001, respectively), and MIG expression was associated with the number of circulating LGLs (r = 0.73; P < .01). The chemokine receptor phenotypes of LDGL cells are essentially similar to those of normal T-cells and NK cells. The roles of IP-10 and MIG in the pathophysiology of LDGL need further examination.
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PMID:Close resemblance between chemokine receptor expression profiles of lymphoproliferative disease of granular lymphocytes and their normal counterparts in association with elevated serum concentrations of IP-10 and MIG. 1787 34

It has previously been demonstrated that there are two distinct mechanisms for genetic resistance to human immunodeficiency virus type 1 (HIV-1) conferred by the CCR5Delta32 gene: the loss of wild-type CCR5 surface expression and the generation of CCR5Delta32 protein, which interacts with CXCR4. To analyse the protective effects of long-term expression of the CCR5Delta32 protein, recombinant lentiviral vectors were used to deliver the CCR5Delta32 gene into human cell lines and primary peripheral blood mononuclear cells that had been immortalized by human T-cell leukemia virus type 1. Blasticidin S-resistant cell lines expressing the lentivirus-encoded CCR5Delta32 showed a significant reduction in HIV-1 Env-mediated fusion assays. It was shown that CD4(+) T lymphocytes expressing the lentivirus-encoded CCR5Delta32 gene were highly resistant to infection by a primary but not by a laboratory-adapted X4 strain, suggesting different infectivity requirements. In contrast to previous studies that analysed the CCR5Delta32 protective effects in a transient expression system, this study showed that long-term expression of CCR5Delta32 conferred resistance to HIV-1 despite cell-surface expression of the HIV co-receptors. The results suggest an additional unknown mechanism for generating the CCR5Delta32 resistance phenotype and support the hypothesis that the CCR5Delta32 protein acts as an HIV-suppressive factor by altering the stoichiometry of the molecules involved in HIV-1 entry. The lentiviral-CCR5Delta32 vectors offer a method of generating HIV-resistant cells by delivery of the CCR5Delta32 gene that may be useful for stem cell- or T-cell-based gene therapy for HIV-1 infection.
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PMID:Resistance to human immunodeficiency virus type 1 (HIV-1) generated by lentivirus vector-mediated delivery of the CCR5{Delta}32 gene despite detectable expression of the HIV-1 co-receptors. 1879 31

The World Health Organization classification of mature T-cell lymphoproliferative disorders, combines clinical, morphological and immunophenotypic data. The latter is a major contributor to the classification, as well as to the understanding of the malignant T-cell behavior. The fact that T-cell migration is regulated by chemokines should, in theory, enable us to identify tissue tropism and organ involvement by neoplastic T-cells by monitoring chemokine receptor surface expression. To address this issue we compared the expression of several early and late inflammatory, homeostatic, and organ specific chemokine receptors on blood T-cells from normal individuals and patients with T-cell large granular lymphocytic leukemia and peripheral T-cell lymphoma. T-cell large granular lymphocytic leukemia cells mainly express late inflammatory chemokine receptors (CXCR1 and CXCR2), whereas peripheral T-cell lymphoma cells usually express one or more organ homing receptors (CCR4, CCR6 and CCR7). Nevertheless, no clear correlation was found between CCR4 and CCR7 expression and skin and lymph node involvement, respectively. Compared to their normal counterparts, lymphoma T-cells displayed an exaggerated CCR4 expression, whereas leukemic T-cells had abnormally high CXCR1 and CXCR2 expression. Further analysis revealed that, in leukemia patients, the percentage of neoplastic cells expressing CCR5 correlates directly with lymphocytosis. In addition, in the case of CD8 T-cell leukemia patients, an inverse correlation with neutropenia was found. In lymphoma patients, higher CCR4 and CCR7 expression is accompanied by lower to absent CCR5 expression.
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PMID:Chemokine receptor repertoire reflects mature T-cell lymphoproliferative disorder clinical presentation. 1884 29


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