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)

Neutralizing antibody (NAb) is a critical component of an immune system that can potentially provide sterilizing protection against human immunodeficiency virus type 1 (HIV-1). Therefore, an in vitro assay that can rapidly, safely, and accurately evaluate the NAb response vaccine candidates elicit, especially against a large number of HIV-1 variants, would be highly valuable. It has been demonstrated that HIV-1 envelope glycoprotein lacking the cytoplasmic domain can pseudotype murine leukemia virus encoding the beta-galactosidase gene and that this pseudovirus can specifically infect CD4(+) cells (Schnierle BS, Stitz J, Bosch V, et al.: Proc Natl Acad Sci USA 1997;94:8640-8645). Because the pseudovirus is not biohazardous and because the infection can be quantitatively determined within 2 days, we examined the feasibility of using the pseudovirus for high-throughput neutralization assays for HIV-1. We have generated viruses pseudotyped with gp140 of six different HIV-1 isolates (LAI, RF, Bal, AD8, 89.6, and DH12). All six pseudoviruses were infectious and exhibited expected coreceptor usage phenotype in HOS-CD4 cells expressing either CCR5 or CXCR4. More importantly, the neutralization sensitivity profile of these pseudoviruses was virtually identical to that observed from more conventional neutralization assays using either HIV-1 or SHIV. All pseudoviruses could be neutralized by broadly reactive human monoclonal antibody IgG1 b12. Our results indicate that the pseudoviruses are ideal for high-throughput evaluation of immune sera for their capacity to broadly neutralize a large number of HIV-1 isolates.
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PMID:Development of a safe and rapid neutralization assay using murine leukemia virus pseudotyped with HIV type 1 envelope glycoprotein lacking the cytoplasmic domain. 1178 23

Feline retrovirus infections have been extensively studied for more than 30 years as an animal model for the persistent infections and pathogenesis caused by retroviruses in general. Two retroviruses, feline leukemia virus (FeLV) and feline immunodeficiency virus (FIV), have been recognized as causative agents of a variety of diseases including proliferative and degenerative diseases. Recent studies revealed the receptors of FeLV, its variants and FIV. FeLVs utilize at least three distinct receptors, two of which have been successfully cloned and characterized. Furthermore, an FeLV variant which induces severe immunodeficiency, utilizes a truncated envelope of the endogenous FeLV as coreceptor or cofactor for viral entry. FIV utilizes as receptor one of the chemokine receptors, CXCR4 which also is a coreceptor for the T-lymphotropic human immunodeficiency virus. This review provides an overview to the infections of FeLV and FIV, specifically focuses on the viral genomic structures, FeLV variants, the immune responses and recent findings on the receptors for FeLV and FIV. Better understanding of retroviral persistence and pathogenesis will aid the development of prophylactic vaccines and therapeutic medicine to interfere with retrovirus infections.
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PMID:Infections of feline leukemia virus and feline immunodeficiency virus. 1181 91

Hematopoietic cells extend multiple podia of yet unknown function. Our morphological studies using scanning electron microscopy and functional studies using time-lapse video microscopy suggest that podia formed by CD34+ hematopoietic stem cells (HSC) on the bone marrow stroma component fibronectin are characteristic of lamellipodia at the leading edge and uropodia at the trailing edge, cytoskeletal structures that have previously been shown to be responsible for cell locomotion of lymphocytes. In the leukemic cells studied here, stroma-derived factor-1alpha (SDF-1alpha) led to a significant eightfold increase in transmigration (BCR-ABL-positive BV173 leukemia cell line; P<0.05) and podia formation in all BCR-ABL-positive leukemic cell lines studied (BV173, K562, 32Dp210) and in two of three BCR-ABL-negative lines (HL60, 32D, not KG1a). We could show that SDF-1alpha exposure led to a down-regulation of the gene expression of the chemokine receptors CCR4, CXCR4, and CXCR5, which are associated with cell motility and podia formation, indicating a negative feedback control. In BCR-ABL-positive leukemic cells, the effects of SDF-1alpha on podia formation and cell migration were independent of BCR-ABL-tyrosine kinase activity. Our data are compatible with the hypothesis that formation of specific podia by hematopoietic cells is associated with egression of these cells from the bone marrow.
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PMID:Functional characterization of podia formation in normal and malignant hematopoietic cells. 1186 80

Chronic lymphocytic leukemia (CLL) is a disease characterized by an accumulation, of mature, functionally incompetent B lymphocytes in the blood, secondary lymphoid tissues, and marrow. Lymphocyte trafficking and homing to specialized microenvironments is an active process that depends on the sequential engagement of adhesion molecules and activation through chemokine receptors. CLL B cells express functional CXCR3, CXCR4, and CXCR5 chemokine receptors that can direct leukemia cell chemotaxis in vitro. Marrow stromal cells, blood-derived "nurse-like cells", and extramedullary stromal cells of mesenchymal origin secrete high amounts of stromal cell-derived factor-1 (SDF-1) and thereby can attract CLL B cells via CXCR4. In vitro, CLL cells are rescued from apoptosis by cell-cell contact with such cells. Moreover, we found that the capacity of these cells to protect leukemia cells from apoptosis in vitro is mediated, at least in part, by the SDF-1 chemokine. Taken together, these findings suggest that chemokines and their receptors on CLL B cells can govern the homing and survival of leukemia B cells in vivo and therefore may contribute to their noted resistance to chemotherapy-induced apoptosis. Conceivably, CXCR4, and possibly other chemokine receptors, may represent a novel target for the development of effective treatment of this disease.
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PMID:Chemokine receptors and stromal cells in the homing and homeostasis of chronic lymphocytic leukemia B cells. 1200 47

Infection of a target cell by HIV is initiated by the interaction of the envelope glycoprotein with the CD4 receptor molecule on the surface of the target cell. This is followed by binding of a coreceptor of the chemokine receptor family and subsequently fusion of viral and cellular membranes. Membrane fusion is independent of whether the viral envelope protein is on the viral or on the cellular membrane. Accordingly, targeting of HIV infected cells by retroviral vectors has been previously achieved both by coincorporation of CD4 and coreceptors into murine leukemia virus (MLV) and lentivirus based vector particles. It was, therefore, tested whether hybrid genes of CD4 and CXCR4 are also able to yield 'receptor' vectors. A construct containing the four extracellular loops of CD4 fused to CXCR4 (CD4-D4-X4) allowed gene transfer into HIV-1 envelope expressing cells by vectors based on either MLV or lentiviruses. The CD4-D2-X4 hybrid receptor, containing the first two extracellular CD4 domains, allowed gene transfer only by lentiviral vectors. Attempts to increase vector titres by deletion of the intracellular part of CXCR4 failed. Vector titres obtained by hybrid receptors were slightly lower than published titres obtained by separate expression of CD4 and CXCR4. Thus, CD4-D4-CXCR4 hybrids are useful for the generation of retroviral and lentiviral vectors with specificity for HIV-1 envelope expressing cells.
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PMID:Specific transduction of HIV-1 envelope expressing cells by retroviral vectors pseudotyped with hybrid CD4/CXCR4 receptors. 1202 Jul 95

The chemokine stromal cell-derived factor 1 (SDF-1) is essential for perinatal viability, B lymphopoiesis, and bone marrow myelopoiesis, and is a potent monocyte and T-lymphocyte chemoattractant. Interactions of SDF-1 with its receptor CXCR4 have been implicated in CD34(+) cell migration and homing. Here it is shown that human SDF-1beta (hSDF-1beta) alone secreted by hSDF-1beta-transduced tumor cells promotes efficacious antitumor responses. The murine C1498 leukemia and B16F1 melanoma models have been studied. For expression of hSDF-1beta by tumor cells (SDF-tumor cells), packaging cell lines secreting retroviruses encoding hSDF-1beta have been used. The results demonstrate that 50% (B16F1) and 90% (C1498) of naive mice injected with SDF-tumor cells reject their tumors. Prophylactic vaccination of naive mice with irradiated SDF-tumor cells leads to systemic immunity, and therapeutic vaccination leads to cure of established tumors. Mice that previously rejected live SDF-tumor cells are immune to the rejected tumor but susceptible to another tumor and have in vitro tumor-specific cytotoxic T lymphocyte (CTL) activity. SDF-tumor cells are not rejected by immunodeficient scid mice. Immunohistochemistry shows significant infiltration of SDF-1 tumors by T cells, and in vivo T-cell depletion studies indicate that CD4(+) T cells are required for SDF-mediated tumor rejection. In conclusion, the present data suggest that SDF-1/CXCR4 interactions have the potential to regulate efficacious antitumor immune responses; exploitation of these interactions may lead to novel therapeutic interventions.
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PMID:Efficacious immunomodulatory activity of the chemokine stromal cell-derived factor 1 (SDF-1): local secretion of SDF-1 at the tumor site serves as T-cell chemoattractant and mediates T-cell-dependent antitumor responses. 1217 69

To develop a reliable strategy for cell-specific delivery of retroviral vectors, we genetically modified the envelope (Env) protein of the ecotropic Moloney murine leukemia virus. We found a site in the variable region A, where the insertion of ligands, epidermal growth factor (EGF) and stromal-derived factor-1 alpha (SDF-1 alpha), was possible without abolishing virion incorporation of the Env protein and its ecotropic entry function. The vector containing the EGF-Env did not show the EGF receptor-dependent transduction. The vector containing the SDF-1 alpha-Env, however, specifically transduced human cells expressing CXCR4, the receptor for SDF-1 alpha, at titers of 10(3)-10(4) c.f.u./ml. Further experiments showed that the CXCR4-dependent transduction was based on the specific interaction between the SDF-1 alpha moiety of the SDF-1 alpha-Env and CXCR4 and was independent of the ecotropic entry function. The direct targeting of the retroviral vector may be possible if the proper chimeric Env structure and the appropriate ligand-receptor system are employed.
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PMID:Factors affecting the direct targeting of murine leukemia virus vectors containing peptide ligands in the envelope protein. 1218 79

Murine leukemia virus (MLV) can be pseudotyped with a variant of the HIV envelope gene encoding the surface glycoprotein gp120-SU and a carboxyl-terminally truncated transmembrane (TM) protein, with only seven cytoplasmic amino acids. MLV/HIV pseudotyped retroviral vectors selectively target human CD4+ cells and can be used as tools to study entry of HIV into cells. Mouse T-cells are immune to HIV infection, which is primarily caused by the weak binding affinity of HIV gp120 to the murine CD4 receptor. Here we show that expression of the human CD4 receptor in murine T-cells is sufficient for syncytia formation with HIV-1 envelope expressing cells and entry of MLV/HIV pseudotyped retroviral vectors. This implies that the murine CXCR4 receptor is a functional coreceptor for MLV/HIV pseudotyped vectors and confirms previous data that the inability of HIV to replicate in murine T-cells is due to a post entry block.
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PMID:Expression of the human CD4 receptor is sufficient for the transduction of murine T-cells with MLV/HIV pseudotyped vectors. 1219 76

Stromal-derived factor (SDF)-1 and its G protein-coupled receptor, CXCR4, regulate stem/progenitor cell migration and retention in the marrow and are required for hematopoiesis. We show here an interaction between CXCR4 and the Src-related kinase, Lyn, in normal progenitors. We demonstrate that CXCR4-dependent stimulation of Lyn is associated with the activation of phosphatidylinositol 3-kinase (PI3-kinase). This chemokine signaling, which involves a Src-related kinase and PI3-kinase, appears to be a target for BCR/ABL, a fusion oncoprotein expressed only in leukemia cells. We show that the binding of phosphorylated BCR/ABL to Lyn results in the constitutive activation of Lyn and PI3-kinase, along with a total loss of responsiveness of these kinases to SDF-1 stimulation. Inhibition of BCR/ABL tyrosine kinase with STI571 restores Lyn responsiveness to SDF-1 signaling. Thus, BCR/ABL perturbs Lyn function through a tyrosine kinase-dependent mechanism. Accordingly, the blockade of Lyn tyrosine kinase inhibits both BCR/ABL-dependent and CXCR4-dependent cell movements. Our results demonstrate, for the first time, that Lyn-mediated pathological crosstalk exists between BCR/ABL and the CXCR4 pathway in leukemia cells, which disrupts chemokine signaling and chemotaxis, and increases the ability of immature cells to escape from the marrow. These results define a Src tyrosine kinases-dependent mechanism whereby BCR/ABL (and potentially other oncoproteins) dysregulates G protein-coupled receptor signaling and function of mammalian precursors.
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PMID:Crosstalk between BCR/ABL oncoprotein and CXCR4 signaling through a Src family kinase in human leukemia cells. 1220 81

Retroviral vectors derived from murine leukemia virus (MLV) have been pseudotyped with a variant of the envelope glycoprotein (Env) of nonpathogenic simian immunodeficiency virus from African green monkeys (SIVagm) to result in [MLV(SIVagm-wt)] vector particles. The variant env gene encodes a full-length surface envelope glycoprotein (SU) and a C-terminally truncated transmembrane protein (TM). To change the coreceptor usage of this vector from CCR5 to CXCR4, which is predominant on human CD4-positive lymphocytes, the putative V3-loop of SIVagm SU was replaced by that of the T cell tropic HIV-1 variant BH10. The resulting [MLV(SIVagm-X4)] vectors were shown to specifically transduce CD4/CXCR4-positive cell lines, demonstrating the equivalent function in cell entry and choice of coreceptor usage of the V3-loops of SIVagm and HIV-1. These modified vectors were able to transduce primary human lymphocytes and were resistant to neutralization by sera from HIV-1-infected individuals. The [MLV(SIVagm-X4)] pseudotype vector generated is thus a promising candidate vector, e.g., for in vivo gene therapy of HIV-1 infection.
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PMID:Coreceptor Switch of [MLV(SIVagm)] pseudotype vectors by V3-loop exchange. 1235 Mar 51


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