Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell-free extracts from human polymorphonuclear neutrophils (PMN) inhibited rebound granulopoiesis in the bone marrow and spleen of mice pretreated with cyclophosphamide to remove endogenous PMN. Absolute numbers of granulocytemonocyte progenitor cells (CFU-C) and net endogenous colony-stimulating activity (CSA) production were found to be increased 3 days after cyclophosphamide in the bone marrow and 6 days after in the spleen. Administration of PMN extract to the drug-treated mice prior to rebound granulopoiesis substantially decreased CSA production and CFU-C but not spleen B lymphocyte colony-forming cells. In addition, mice treated with PMN extract had decreased levels of CSA in serum and in conditioned medium of marrow-free bone, heart, and lung cultures. Inhibition was reversed by injection of bacterial lipopolysaccharide. Extracts from PMN of patients with chronic myelogenous leukemia, inactive in vitro, had no effect in vivo. These results demonstrate that inhibitory activity derived from PMN can control granulopoiesis in vivo.
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PMID:Inhibition in vivo of mouse granulopoiesis by cell-free activity derived from human polymorphonuclear neutrophils. 63 51

A patient with Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) entered a blast crisis localized to lymph nodes. On light microscopy, by morphology and histochemical staining, the blasts were undifferentiated. In spite of terminal deoxynucleotidyl transferase positivity, some of the lymph node cells expressed a myeloid differentiation antigen, OKM1, and were peroxidase positive by transmission electron microscopy (TEM). However, the majority of cells were peroxidase negative on TEM and expressed OKT-10, a marker found on both primitive myeloid and lymphoid cells. Cultures of lymph node cells stimulated with Epstein-Barr virus or lipopolysaccharide (LPS) revealed the Ph1, indicating B cell involvement in the CML. T cells from cultures stimulated with L4-phytohemagglutinin and T cell growth factor were negative for the Ph1. In unstimulated lymph node cells, the uncomplicated Ph1 could not be demonstrated; instead, a unique complex karyotype involving a masked Ph1 was identified in these and the LPS cultures. This karyotype was not found in bone marrow (BM) metaphase cells. Instead, BM cells showed either the simple Ph1 or the Ph1 with a rearrangement involving chromosomes 13 and 20. The patient had transient responses to three chemotherapy regimens, two of which were designed to treat acute lymphocytic leukemia, but he died 8 months after disease acceleration without BM blast crisis. These findings are compatible with an extramedullary blast crisis originating in a primitive cell with both myeloid and lymphoid characteristics.
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PMID:Unusual karyotypic changes and B cell involvement in a case of lymph node blast crisis of chronic myelogenous leukemia. 661 Apr 45

Interleukin-8 (IL-8) is produced by many cell types upon stimulation with bacterial products or inflammation-associated cytokines such as tumor necrosis factor-alpha and IL-1. Interferons (IFNs) represent another group of cytokines that are induced by similar stimuli in inflammatory reactions. We show now that type-I IFNs are potent inhibitors of IL-8 expression in vitro and in vivo. A significant reduction of both secretion of IL-8 protein and accumulation of IL-8 mRNA in vitro was observed in several cell types comprising peripheral blood mononuclear cells (PBMNC) from healthy donors and from patients with chronic myelogenous leukemia (CML), the myelomonocytic cell line THP-1, and bone marrow (BM) stromal cells as a representative model for BM microenvironment. By contrast, in lipopolysaccharide-stimulated polymorphonuclear phagocytes IFN failed to suppress IL-8 expression. In untreated patients with CML, a constitutive expression of IL-8 mRNA was detected in freshly isolated PBMNC that was markedly reduced 5 hours after therapeutic application of IFN-alpha. The mechanism of IL-8 downregulation was studied more in detail in the THP-1 cell line. The experiments showed that de novo protein synthesis was not required for the inhibitory effect. RNA decay analysis and nuclear run-on assays suggest that in THP-1 cell line the inhibition of IL-8 expression is predominantly regulated at the posttranscriptional level.
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PMID:Type-I interferons are potent inhibitors of interleukin-8 production in hematopoietic and bone marrow stromal cells. 840 Feb 88

The intactness of monocyte function in chronic myeloid leukemia (CML) patients as assessed by their ability to secret tumor necrosis factor was evaluated. Monocytes from CML patients continued to respond to lipopolysaccharide (LPS) stimulation even during the refractory period, suggesting different pathways for stimulation by LPS and malignant processes.
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PMID:Tumor necrosis factor as marker for monocyte function in chronic myeloid leukemia. 863 Jun 84

Mice with a null mutation of the gene encoding interferon consensus sequence-binding protein (ICSBP) develop a disease with marked expansion of granulocytes and macrophages that frequently progresses to a fatal blast crisis, thus resembling human chronic myelogenous leukemia (CML). One important feature of CML is decreased responsiveness of myeloid cells to apoptotic stimuli. Here we show that myeloid cells from mice deficient in ICSBP exhibit reduced spontaneous apoptosis and a significant decrease in sensitivity to apoptosis induced by DNA damage. In contrast, apoptosis in thymocytes from ICSBP-deficient mice is unaffected. We also show that overexpression of ICSBP in the human U937 monocytic cell line enhances the rate of spontaneous apoptosis and the sensitivity to apoptosis induced by etoposide, lipopolysaccharide plus ATP, or rapamycin. Programmed cell death induced by etoposide was specifically blocked by peptides inhibitory for the caspase-1 or caspase-3 subfamilies of caspases. Studies of proapoptotic genes showed that cells overexpressing ICSBP have enhanced expression of caspase-3 precursor protein. In addition, analyses of antiapoptotic genes showed that overexpression of ICSBP results in decreased expression of Bcl-X(L). These data suggest that ICSBP modulates survival of myeloid cells by regulating expression of apoptosis-related genes.
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PMID:Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein. 1043 Jun 29

The axl tyrosine kinase receptor is aberrantly expressed on myeloid cells of many individuals afflicted with chronic myelogenous leukemia (CML) and other myeloid leukemias. Although previous studies demonstrated this kinase to have oncogenic potential, it is not known whether axl actively participates in the onset and/or progression of CML. We addressed this question by generating transgenic mice possessing constitutive ectopic expression of human axl throughout cells of the myeloid hematopoietic lineage through the use of the granulocyte colony-stimulating factor (GCSF) receptor promoter. The transgenics did not exhibit hematopoietic malignancies, but did exhibit phenotypic characteristics associated with noninsulin-dependent diabetes mellitus (NIDDM) including hyperglycemia and hyperinsulinemia, severe insulin resistance, progressive obesity, hepatic lipidosis, and pancreatic islet dysplasia. The obese-diabetes phenotype was similar to that observed in the agouti and melanocortin-4(-/-) mutants, however the axl transgenics were not hyperphagic. Axl transgenic animals expressed elevated serum tumor necrosis factor (TNF)-alpha levels that were further enhanced upon in vitro lipopolysaccharide (LPS) stimulation of peripheral blood. Administration of the axl ligand, gas6, to peripheral transgenic blood samples eliminated excessive TNF-alpha production in response to LPS stimulation. As a means to better understand axl-gas6 biology, transgenic animals were produced which systemically expressed the gas6-binding axl proteolytic cleavage product. A more severe NIDDM phenotype occurred in these mice. The observed phenotypes may be related to the axl receptor or proteolytic cleavage product competing with related axl family receptors for binding of the gas6 ligand. We conclude that axl expression in myeloid cells in itself does not lead to the onset or progression of leukemia and suggest that ectopic axl expression affects endogenous modulation of TNF-alpha production indirectly resulting in the NIDDM phenotype.
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PMID:Noninsulin-dependent diabetes mellitus occurs in mice ectopically expressing the human Axl tyrosine kinase receptor. 1052 29

Leukemic cells proliferate under the influence of cytokines. In particular, the colony-stimulating factors stimulate the growth and proliferation of myeloid leukemia cells. Under normal conditions, tumor necrosis factor-alpha (TNF-alpha) is produced by activated monocytes, whereas interleukin- 10 (IL-10) is produced by several cell types like monocytes and lymphocytes. The autocrine production of cytokines by leukemic cells may have a pathogenic role in the progression of leukemia or may be an epiphenomenon. In this study, we investigated the expression of TNF-alpha and IL-10 in human leukemic cells by RT-PCR and by a cytoplasmic protein assay. Most cases of acute myelogenous leukemia (AML) (7/8 cases) and all cases of acute lymphoblastic leukemia (ALL) (n = 2), chronic myelogenous leukemia (CML) (n = 5), both in chronic phase and during blast crisis, expressed the mRNA for TNF-alpha and IL-10. A patient whose blasts were positive for IL-10 and negative for TNF-alpha, had high circulating levels of IL-10 and failed to respond to donor lymphocyte infusions. Using a cytoplasmic protein assay, generally low levels of cytoplasmic TNF-alpha and IL-10 were found which increased in case of TNF-alpha following stimulation with lipopolysaccharide. Taken together, our data show that most leukemic cells express the mRNA for a proinflammatory cytokine (TNF-alpha) and an immunosuppressive cytokine (IL-10). More work is necessary to determine under which conditions these cytokines actually paralyze the immune system and thereby permit the progression of leukemia.
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PMID:Different types of human leukemias express the message for TNF-alpha and interleukin-10. 1154 18

Chronic myeloid leukaemia (CML) dendritic cells (DC) are possible candidates for inducing antileukaemic immunity. This study aimed to investigate the frequency, phenotype and function of blood-derived leukaemic DC in comparison with DC from healthy donors using flow cytometric assays and mixed leucocyte reaction (MLR). Immature leukaemic DC displayed a reduced endocytotic capacity as compared with healthy controls. Moreover, in vitro maturation of leukaemic DC was found to be deficient. Expression of CD80, CD83, CD86, and major histocompatibility complex class I and class II antigens were reduced on lipopolysaccharide (LPS)-matured leukaemic DC but were enhanced by a mixture of interleukin 1beta (IL-1beta), IL-6, tumour necrosis factor-alpha (TNF-alpha) and prostaglandin E2 (PGE2). Upon stimulation with bacterial LPS, intracellular TNF-alpha and IL-8 production was diminished in maturing DC from CML patients. This distinct cytokine deficiency was overcome when leukaemic DC were stimulated with cytokines/PGE2. MLR showed fully functional leukaemic DC after TNF-alpha-induced maturation, but a reduced proliferative alloresponse of leukaemic peripheral blood mononuclear cells. Further, intracellular production of cytokines in CML-derived T cells was markedly reduced. These data indicated that, in CML, the maturation response of leukaemic monocyte-derived DC to a natural stimulus like LPS is abnormal and may be caused by an aberrant TNF-alpha response in these cells. Thus, TNF-alpha alone or in combination with pro-inflammatory and T-cell stimulatory cytokines should be considered as an adjuvant for DC-based immunotherapy in CML.
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PMID:Phenotypic and functional deficiencies of leukaemic dendritic cells from patients with chronic myeloid leukaemia. 1249 78

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from the clonal expansion of a stem cell expressing the bcr/abl oncogene. CML patients frequently respond to treatment with interferon-alpha (IFN-alpha), even though the mechanisms of the response remain unclear. In the present study, we evaluated the role of IFN-alpha in differentiation and activity of monocyte-derived dendritic cells (DCs) from CML patients as well as in modulation of the cell response to lipopolysaccharide (LPS). Treatment of CML monocytes with IFN-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in the rapid generation of activated DCs (CML-IFN-DCs) expressing interleukin-15 (IL-15) and the antiapoptotic bcl-2 gene. These cells were fully competent to induce IFN-gamma production by cocultured autologous T lymphocytes and expansion of CD8(+) T cells. LPS treatment of CML-IFN-DCs, but not of immature DCs generated in the presence of IL-4/GM-CSF, induced the generation of CD8(+) T cells reactive against autologous leukemic CD34(+) cells. Altogether, these results suggest that (1) the generation of highly active monocyte-derived DCs could be important for the induction of an antitumor response in IFN-treated CML patients and (2) IFN-alpha can represent a valuable cytokine for the rapid generation of active monocyte-derived DCs to be utilized for vaccination strategies of CML patients.
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PMID:IFN-alpha promotes the rapid differentiation of monocytes from patients with chronic myeloid leukemia into activated dendritic cells tuned to undergo full maturation after LPS treatment. 1452 81

Peptide-pulsed dendritic cells can stimulate T cells showing specific cytotoxicity in chronic myelogenous leukemia. We tried to induce a specific cytotoxic T-cell response stimulated by RNA-pulsed dendritic cells in acute myelogenous leukemia. The total RNA of WEHI-3BD+, a myelomonocytic leukemia cell line derived from BALB/c mice, was transfected into dendritic cells induced from bone marrow nucleated cells of BALB/c mice with granulocyte macrophage colony-stimulating factor (GM-CSF) and lipopolysaccharide (LPS) using liposome. RNA-pulsed dendritic cells were injected into the peritoneal cavity of BALB/c mice, and splenic T cells were isolated for antigen-stimulated proliferation and leukemia-specific cytotoxicity assay. Cultured bone marrow nucleated cells expressed dendritic cell markers including MHC class II antigen, CD80, CD86, and CD11c. T cells stimulated by RNA-pulsed dendritic cells showed enhanced proliferation than those stimulated by unpulsed dendritic cells (P = 0.05) and showed dose-dependent specific cytotoxicity against WEHI-3BD+ cells. We concluded total RNA-pulsed dendritic cells could induce a specific T-cell cytotoxicity in acute myelogenous leukemia.
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PMID:Induction of cytotoxic T lymphocytes by dendritic cells pulsed with murine leukemic cell RNA. 1497 90


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