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)

Adult T-cell leukemia (ATL) is an aggressive malignancy of CD4(+) T cells caused by the human T-cell leukemia virus type 1 (HTLV-1). The viral leukemogenesis is critically dependent on its oncoprotein Tax because the protein as well as the virus can immortalize primary human lymphocytes to permanent growth. As a transcriptional transactivator, Tax can stimulate the expression of distinct cellular genes. Alterations in the expression levels of unknown growth-relevant genes may contribute to the changed growth properties of Tax-immortalized and leukemic cells. To identify genes that are linked to Tax transformation and ATL leukemogenesis, this study systematically compared the gene expression of cultured cells from patients with acute ATL with that of stimulated peripheral blood T lymphocytes. Several overexpressed RNAs that encode signal transduction functions were identified. These include a dual-specific protein phosphatase (PAC1), an interferon-inducible factor (ISG15), a basic helix-loop-helix transcription factor (DEC-1), and the secreted antiapoptotic chemokine I-309. The ATL cell culture supernatants contained an antiapoptotic activity that could be specifically inhibited by antibodies directed against I-309. Inhibition of I-309 receptor (CCR8) signaling by pertussis toxin increased the apoptosis rate of ATL cell cultures in the presence and absence of external apoptotic stimuli. Both the I-309--specific antiapoptotic activity and the proapoptotic effect of inhibitors of I-309 signaling suggest the existence of an antiapoptotic autocrine loop in ATL cells. Thus, the overexpression of this chemokine may inhibit apoptosis in ATL cells and could substantially contribute to their growth. (Blood. 2001;98:1150-1159)
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PMID:Autocrine antiapoptotic stimulation of cultured adult T-cell leukemia cells by overexpression of the chemokine I-309. 1149 64

Dendritic cells (DC), the most potent antigen-presenting cells (APC), have been implicated as the initial targets of HIV infection in skin and mucosal surfaces. DC can be generated in vitro from blood-isolated CD14(+) monocytes or CD34(+) hematopoietic progenitor cells in the presence of various cytokines. In this study, we investigated whether monocytes obtained from placental cord blood are capable of differentiation into dendritic cells when cultured with a combination of cytokines - granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF-alpha). We then examined HIV infection, HIV receptor (CD4, CCR5) expression, and beta-chemokine [macrophage inflammatory protein-1alpha and -1beta (MIP-1alpha, MIP-1beta)] production by placental cord monocyte-derived dendritic cells (MDDC) as compared to that of autologous cord monocyte-derived macrophages (MDM). Monocytes isolated from placental cord blood differentiate into DC after 7 days in culture with the mixture of cytokines, as demonstrated by development of characteristic DC morphology, loss of CD14 expression, and gain of CD83, a marker for mature DC. Mature cord MDDC had significantly lower susceptibility to M-tropic ADA (CCR5-dependent) envelope-pseudotyped HIV infection in comparison to autologous placental cord MDM, whereas there was no significant difference in virus replication in cord MDDC and MDM infected with murine leukemia virus envelope-pseudotyped HIV (HIV receptor-independent). This limited susceptibility of cord MDDC to M-tropic HIV infection may be due to lower expression of CD4 and CCR5 on the cell membrane and higher production of MIP-1alpha and MIP-1beta. These data provide important information toward our understanding of the biological properties of cord MDDC in relation to HIV infection.
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PMID:HIV-1 infection of placental cord blood monocyte-derived dendritic cells. 1167 7

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

Chemokines and chemokine receptors play important roles in migration and tissue localization of various lymphocyte subsets. Here, we report the highly frequent expression of CCR4 in adult T-cell leukemia (ATL) and human T-cell leukemia virus type 1 (HTLV-1)-immortalized T cells. Flow cytometric analysis revealed that ATL and HTLV-1-immortalized T-cell lines consistently expressed CCR4. Inducible expression of HTLV-1 transcriptional activator tax in a human T-cell line Jurkat did not, however, up-regulate CCR4 mRNA. In vitro immortalization of peripheral blood T cells led to preferential outgrowth of CD4(+) T cells expressing CCR4. We further demonstrated highly frequent expression of CCR4 in fresh ATL cells by (1) reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of CCR4 expression in peripheral blood mononuclear cells (PBMCs) from patients with ATL and healthy controls; (2) flow cytometric analysis of CCR4-expressing cells in PBMCs from patients with ATL and healthy controls; (3) CCR4 staining of routine blood smears from patients with ATL; and (4) an efficient migration of fresh ATL cells to the CCR4 ligands, TARC/CCL17 and MDC/CCL22, in chemotaxis assays. Furthermore, we detected strong signals for CCR4, TARC, and MDC in ATL skin lesions by RT-PCR. Collectively, most ATL cases have apparently derived from CD4(+) T cells expressing CCR4. It is now known that circulating CCR4(+) T cells are mostly polarized to Th2 and also contain essentially all skin-seeking memory T cells. Thus, HTLV-1-infected CCR4(+) T cells may have growth advantages by deviating host immune responses to Th2. CCR4 expression may also account for frequent infiltration of ATL into tissues such as skin and lymph nodes.
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PMID:Frequent expression of CCR4 in adult T-cell leukemia and human T-cell leukemia virus type 1-transformed T cells. 1186 Dec 61

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

Platelet activating factor (PAF) interacts with cell surface G protein-coupled receptors on leukocytes to induce degranulation, leukotriene C(4) (LTC(4)) generation, and chemokine CCL2 production. Using a basophilic leukemia RBL-2H3 cell line expressing wild-type PAF receptor (PAFR) and a phosphorylation-deficient mutant (mPAFR), we have previously demonstrated that receptor phosphorylation mediates desensitization of PAF-induced degranulation. Here, we sought to determine the role of receptor phosphorylation on PAF-induced LTC(4) generation and CCL2 production. We found that PAF caused a significantly enhanced LTC(4) generation in cells expressing mPAFR when compared with PAFR cells. In contrast, PAF-induced CCL2 production was greatly reduced in mPAFR cells. Pertussis toxin and U0126, which inhibit G(i) and p44/42 mitogen-activated protein kinase (ERK) activation, respectively, caused very little inhibition of PAF-induced CCL2 production (approximately 20% inhibition). In contrast, these inhibitors almost completely blocked both PAF-induced ERK phosphorylation and LTC(4) generation in PAFR cells. However, in mPAFR cells pertussis toxin only partially inhibited PAF-induced ERK phosphorylation. A Ca(2+)/calmodulin inhibitor had no effect on PAF-induced ERK phosphorylation in PAFR cells but completely blocked the response in mPAFR cells. These data demonstrate that receptor phosphorylation, which serves to desensitize PAF-induced LTC(4) generation, is required for chemokine CCL2 production. They also indicate a previously unrecognized selectivity in G protein usage and ERK activation for PAF-induced responses. Whereas PAF-induced CCL2 production is, in large part, mediated independently of G(i) activation or ERK phosphorylation, LTC(4) generation requires ERK phosphorylation, which is mediated by different G proteins depending on the phosphorylation status of the receptor.
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PMID:Distinct roles of receptor phosphorylation, G protein usage, and mitogen-activated protein kinase activation on platelet activating factor-induced leukotriene C(4) generation and chemokine production. 1193 80

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor CXCR-4 contribute to stem cell homing and may play a role in the trafficking of leukemic cells. Therefore, we analyzed migration across Transwell filters of cells derived from bone marrow (BM) or peripheral blood (PB) from 26 acute myeloid leukemia (AML) patients. The presence of the extracellular matrix protein fibronectin (FN) strongly enhanced the spontaneous and SDF-1-induced migration of leukemic PB and BM cells. No differences in spontaneous, SDF-1-induced migration or CXCR-4 expression were observed between the different AML subtypes. Subsequently, it was determined whether SDF-1 preferentially promoted migration of subsets of leukemic cells. Leukemic cells expressing CD34, CD38 and HLA-DR were preferentially migrating, whereas cells expressing CD14 and CD36 showed diminished migration. Analysis of paired PB and BM samples indicated that significantly higher SDF-1-induced migration was observed in AML for CD34(+) BM-derived cells compared to CD34(+) PB-derived cells, suggesting a role for SDF-1 in the anchoring of leukemic cells in the BM or other organs. The lower percentage of circulating leukemic blasts in patients with a relatively high level of SDF-1-induced migration also supports this hypothesis. In conclusion, we have shown that primary AML cells are migrating towards SDF-1 independent of the AML subtypes.
Leukemia 2002 Apr
PMID:Migratory behavior of leukemic cells from acute myeloid leukemia patients. 1196 Mar 46

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

All-trans retinoic acid (ATRA) has been shown to induce differentiation of human acute promyelocytic leukaemia (APL) cells and eventual elimination of the malignant clone. Matrix metalloproteinase-9 (MMP-9) is produced by neutrophils and its expression appears to be linked with myeloid cell differentiation. We investigated effects of ATRA on MMP expression in two human myeloid leukaemia cell lines, PL-21 and NB4. Both cells could differentiate into neutrophils after exposure to ATRA. Both the activity and antigen levels of MMP-9 were much higher in NB4 cells than in PL-21 cells. Stimulation with ATRA significantly increased MMP-9 levels approximately three- to fivefold in both PL-21 and NB4-conditioned media. MMP-9 mRNA levels increased in ATRA-treated cells and was almost in parallel with the increase in MMP-9 activity, suggesting that ATRA induced MMP-9 by activating its gene expression. ATRA can induce interleukin 8 (IL-8) in APL cells. IL-8, chemokine for neutrophils and a potent inducer of MMP-9, was also induced by ATRA in PL-21 cells. However, recombinant IL-8 did not induce MMP-9 expression. In addition, a neutralizing antibody against IL-8 did not inhibit ATRA-induced MMP-9 expression in either cell type. These observations suggest that ATRA can induce both MMP-9 and IL-8, but IL-8 is not involved in ATRA-induced MMP-9 expression. As MMP-9 can truncate and activate IL-8, simultaneous induction of MMP-9 and IL-8 by ATRA could activate leucocytes excessively, causing the hyper-inflammatory events in retinoic acid syndrome.
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PMID:Simultaneous induction of matrix metalloproteinase-9 and interleukin 8 by all-trans retinoic acid in human PL-21 and NB4 myeloid leukaemia cells. 1213 25

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


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