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)

Strong and heritable increase of immunogenicity of L1210 Ha leukemia has been obtained in vitro following multiple treatments with 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), metabolically activated by mouse liver preparations (MLP) containing liver microsomes. The DTIC-treated leukemia (L1210D line) or the control line treated with MLP alone (L1210N line) showed comparable growth kinetics in vitro. However, progressive increase of immunogenicity occurred in leukemic cells in the course of in vitro treatments with DTIC plus MIP, but not with MLP alone, as evidenced by comparative studies on transplantation immunity elicited in BALB/c x DBA/2 F1 mice by graded inocula of L1210D or L1210N leukemia cells. In vitro experiments confirmed that metabolic transformation of DTIC is required for increasing tumor immunogenicity. In fact, L1210Ha cells became highly immunogenic when treated with DTIC in intact mice but not in animals metabolically depressed by CCl4. Immunochemotherapy experiments based on the antigenic cross-reactivity between the L1210D line and the original L1210Ha leukemia showed that i.p. administration of L1210D cells followed by 1,3-bis(2-chloroethyl)-1-nitrosourea treatment afforded marked protection in mice inoculated intracerebrally with the parental lymphoma. The present findings could provide an adequate in vitro technique for developing further studies on DTIC-mediated immunogenic changes of tumors, including human cancer cells growing in tissue culture.
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PMID:In vitro generation of a highly immunogenic subline of L1210 leukemia following exposure to 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide. 701 15

The myelosuppressive effects of human chemokines were evaluated in vitro on normal myeloid progenitors obtained from bone marrow and cord blood, on bone marrow progenitors from patients with acute or chronic leukemia, on proliferation of human factor-dependent cell line M07e, and in vivo on myelopoiesis in mice. Preincubation of human MIP-1 alpha, MIP-2 alpha, interleukin (IL)-8, platelet factor (PF) 4, monocyte chemotactic and activating factor (MCAF), and interferon-inducible protein-10 (IP-10) in an acetonitrile (ACN) solution significantly enhanced the specific activity of these chemokines for in vitro suppression of granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and multipotential (CFU-GEMM) progenitor cells stimulated to proliferate with a colony stimulating factor plus steel factor (SLF). Combinations of any two of these ACN-treated chemokines synergized to suppress colony formation of CFU-GM, BFU-E, and CFU-GEMM at chemokine concentrations below that at which combinations of non-ACN treated chemokines are active. Cord blood progenitors, as previously reported, were in a slow or noncycling state and nonresponsive to inhibition by chemokines. However, after suspension culture with GM-CSF, IL-3, and SLF, they were placed into rapid cell cycle and were responsive to inhibition by ACN-treated chemokines. Low doses of these ACN-pretreated chemokines were active in vivo in suppressing absolute numbers and cycling status of femoral marrow CFU-GM, BFU-E, and CFU-GEMM in C3H/HeJ mice. Other chemokines, alone and in combination, including MIP-1 beta, MIP-2 beta, GRO-alpha NAP-2, and RANTES, were inactive in vitro and in vivo whether or not they were pretreated with ACN. While heterogeneity in responsiveness of CFU-GM from different patients with leukemia to suppression by ACN-treated chemokines was apparent, if the patients had CFU-GM responsive to one of the active chemokines these cells were responsive to the other active chemokines; if patient CFU-GM were not responsive to one of the chemokines, they were not responsive to the other active chemokines. M07e colony-forming cells were responsive to the growth-inhibiting effects of the active ACN-treated chemokines, alone and in combination, but these effects were rapidly reversible and sustained only by multiple daily additions of chemokines. These results should be of value in considering these chemokines for potential clinical use and for assessment of their mechanisms of action, alone and in combination.
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PMID:Human chemokines: enhancement of specific activity and effects in vitro on normal and leukemic progenitors and a factor-dependent cell line and in vivo in mice. 749 26

Chemoattractants, including chemokines such as interleukin 8 (IL-8) and related proteins, activate leucocytes via seven-transmembrane-domain G-protein-coupled receptors. A cDNA for a novel receptor of this kind consisting of 327 amino acids was isolated from a human blood monocyte cDNA library. The polypeptide, termed monocyte-derived receptor 15 (MDR15), is an alternative form of the Burkitt's lymphoma receptor 1 (BLR1) encoded by a human Burkitt's lymphoma cDNA [Dobner, Wolf, Emrich and Lipp (1992) Eur. J. Immunol. 22, 2795-2799]. MDR15 and BLR1 cDNAs differ in the 5' region, where the open reading frame of MDR15 is shorter by 45 codons. Southern-blot analysis indicates that the two transcripts for MDR15 and BLR1 are encoded by the same gene. Northern-blot analysis using a probe that hybridizes with both mRNAs demonstrated high-level expression in chronic B-lymphoid leukaemia and non-Hodgkin's lymphoma cells and, to a lesser extent, peripheral blood monocytes and lymphocytes. Reverse transcription-PCR studies with MDR15- and BLR1-specific primers showed similar levels of transcripts for both receptors in RNA that was positive in Northern-blot analysis. MDR15 and BLR1 have high structural similarity to receptors for human IL-8 (about 40% amino acid identity) and other chemokines. However, none of a series of radiolabelled chemokines (IL-8, NAP-2, GRO alpha, PF4, IP10, MCP-1, MCP-2, MCP-3, I-309, RANTES and MIP-1 alpha) and other ligands (C3a and leukotriene B4) bound to Jurkat transfectants that stably expressed either MDR15 or BLR1 mRNA. The fact that MDR15 and BLR1 are expressed on leucocytes and show marked sequence similarity to chemokine receptors suggests the existence of as yet unidentified chemokines. Alternative transcript formation affecting the 5'-terminal part of the coding region may be a way to modify ligand-binding selectivity.
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PMID:Sequence variation of a novel heptahelical leucocyte receptor through alternative transcript formation. 763 92

A human cDNA encoding a putative G protein-coupled receptor designated chemokine beta receptor-like 1 (CMKBRL1) was isolated from an eosinophilic leukemia library. Its deduced sequence is approximately 40% identical to previously cloned receptors for the beta chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha), RANTES, and monocyte chemoattractant protein-1 (MCP-1), which are chemoattractants for blood leukocytes, and is 83% identical to the product of the orphan rat cDNA RBS 11. Like the MIP-1 alpha/RANTES receptor, CMK-BRL1 is encoded by a small, single-copy gene that maps to chromosome 3p21 and is expressed in leukocytes. However, two screening assays with a broad panel of chemokines failed to identify its ligand. CMKBRL1 mRNA was detectable by Northern blot hybridization in neutrophils and monocytes, but not eosinophils, and was also found in eight solid organs that were tested with particularly high expression in brain. The RNA distribution of the known beta chemokine receptors was overlapping but distinct from that of CMKBRL1. MIP-1 alpha/RANTES receptor mRNA was detectable in neutrophils, monocytes, eosinophils, and in all eight solid organs tested, with particularly high expression in placenta, lung, and liver. MCP-1 receptor mRNA was found in monocytes, lung, liver, and pancreas. These results suggest that the ligand for the putative CMKBRL1 receptor is a beta chemokine that targets both neutrophils and monocytes. Moreover, the RNA distributions suggest that CMKBRL1, the MIP-1 alpha/RANTES receptor, and the MCP-1 receptor may have both overlapping and distinct biological roles.
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PMID:Cloning, chromosomal localization, and RNA expression of a human beta chemokine receptor-like gene. 764 14

To determine the role of infected marrow accessory cells in the pathogenesis of viral-associated hematologic disorders, we evaluated whether feline leukemia virus (FeLV) infection alters the cytoadhesive properties of long-term marrow culture (LTMC) stromal cells, the support of stromal-associated progenitors in LTMCs, and the production of progenitor growth-promoting and -inhibiting activities by marrow stromal cells. Our previous studies demonstrated that LTMCs containing FeLV-infected stromal cells generated two- to three-fold higher numbers of total nonadherent cells and nonadherent granulocyte-macrophage progenitors (CFU-GM) compared with uninfected LTMCs. In the present studies, CFU-GM and primitive erythroid progenitors (BFU-E) bound equivalently to FeLV-infected or uninfected LTMC stromal cells in a 2-hour adherence assay. In recharge LTMC studies, the numbers of adherent CFU-GM maintained in cultures containing stromal cells infected with FeLV-A/61E were not significantly different from controls (range 84-191% of uninfected control cultures, p > 0.1); however, the percentages of adherent CFU-GM in S phase of the cell cycle were consistently increased (range 42-62% compared with controls, range 5-23%). FeLV infection had no significant effect on the cell-cycle status of the nonadherent CFU-GM in LTMCs. Agar co-culture assays revealed that multilineage colony-stimulating activity was constitutively and equivalently produced by feeder cell layers consisting of either uninfected or FeLV-infected irradiated heterogeneous LTMC stromal cells, homogeneous marrow stromal fibroblasts, or a fibroendothelial marrow stromal cell line. However, FeLV infection significantly attenuated the soluble progenitor growth-inhibitory activity associated with higher densities of these stromal cells. Assays of conditioned medium from cultures of irradiated stromal cells demonstrated that FeLV infection or hydrocortisone exposure decreased the utilization of glucose, the production of acidic metabolic products, and the constitutive production of active and latent transforming growth factor beta (TGF-beta) bioactivity and TGF-beta 2 immunoreactivity. Levels of macrophage inflammatory protein 1 alpha (MIP-1 alpha) and tumor necrosis factor alpha (TNF-alpha) were undetectable and unchanged in CM samples. Together, these observations suggest that downmodulation of TGF-alpha and/or the basal metabolic status of stromal cells may be responsible for the high basal proliferative activity of adherent CFU-GM in FeLV-infected LTMCs, and by extension, that retroviral infection in vivo could alter hematopoiesis by perturbing the progenitor growth-regulatory and -supportive function of marrow stromal cells.
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PMID:Feline leukemia virus infection downmodulates the production of growth-inhibitory activity by marrow stromal cells. 765 28

To date no hematopoietic progenitors of dendritic Langerhans' cells (DLC), which represent an highly efficient class of antigen presenting cells, have been identified or the cytokines they elaborate have been defined. Here we describe an acute leukemia patient whose blasts (90-96% in peripheral blood and bone marrow) had a phenotype consistent with putative progenitors of DLC. The patient was treated with ara-C and VP-16 but did not achieve remission. The blasts had lobulated nuclei, no cytoplasmic vacuolation or Auer rods and were weakly positive for acid phosphatase and non-specific esterase and negative for PAS, granzyme A, dipeptidyl aminopeptidase IV, ATPase/ADPase and lysozyme production. The blasts were positive for CD1a, CD4, CD16, CD35, HLADR, HLADQ, CD11b, CD11c, CD14, CD33, CD34, CD11a, CD71, CD19, CD25, IL-2R beta and negative for CD2, CD7, CD8, CD10, CD22, CD56, CD57, surface or cytoplasmic CD3, TCR delta and TCR beta, HTLV-1p19 and P-glycoprotein. On liquid culture with or without 5 x 10(-9) M 12-O-tetradecanoylphorbol-13-acetate (TPA) for 3 days, the blasts formed aggregates of proliferating and elongating cells on the wall of the flasks with a decline in CD34, numerous dendritic processes appeared on the cells and there was strong positivity for ATPase/ADPase, but no other changes in phenotype. No macrophages were observed, indicating derivation from separate DLCs. Cytogenetic analysis showed chromosomal abnormalities and electron microscopy showed Birbeck granules. Southern blotting of DNA showed rearrangement of one allele for both JH and TCR beta but no HTLV-1 related sequences. Culture supernatants from blasts cultured with or without TPA showed the production of large amounts of IL-8, IL-6, TNF-alpha, MIP-1 alpha, IL-10 and interferon gamma and modest amounts of IL-1 alpha, GM-CSF and stem cell factor. The presence not only of CD1a, HLADR, HLADQ and many other characteristics including Birbeck granules, but also differentiation along the lines of DLC with appearance of dendritic processes on the cells and expression of ATPase/ADPase activity, indicate that the leukemic blasts in our patient represented a leukemic counterpart of normal progenitors of DLC and the leukemia a new entity which could possibly be classified as AML-M8. Lastly, many pro-inflammatory cytokines produced by DLC could contribute to inflammation and IL-10 to immunosuppression.
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PMID:Phenotype, genotype and cytokine production in acute leukemia involving progenitors of dendritic Langerhans' cells. 791 55

The pX gene of human T-cell leukemia virus type I (HTLV-I) is known to be a potent transactivator of the viral gene and the host genes which are important for cell proliferation in vitro. It has been reported that various diseases occur in transgenic mice harboring either tax, pX, or env-pX gene, such as mesenchymal tumor, neurofibroma, thymic atrophy, muscle degeneration, exocrinopathy and arthropathy. We previously demonstrated that rat but not mouse CD4 positive T cells could be easily infected and immortalized by HTLV-I and infectious transmission of HTLV-I induced HAM/TSP-like myelopathy in WKAH rats after long incubation periods of 16 months. These observations prompted us to produce a series of transgenic rats that expressed the pX gene products under the control of mouse H-2Kd promotor in order to evaluate further the biological and pathological function of the pX gene in vivo. In various tissues of pX transgenic rats (pX rats), pX mRNA was constitutively expressed irrespective of age. PX rats developed mammary tumors with massive infiltration by neutrophils as early as 9 months of age. Pathological and immunohistochemical examination revealed that the tumors were undifferentiated carcinomas of the mammary gland origin. They were transplantable into pX rats, but not into normal syngenic rats. High levels of mRNA expression of not only the pX transgene but also the host genes such as Gro (melanoma growth-stimulatory activity/KC), MIP-2 (macrophage inflammatory protein-2) and IL-1 alpha were demonstrated in the tumor tissues. Gro and MIP-2 which were known as IL-8 families were likely to be produced by tumor cells and appeared to be responsible for neutrophil infiltration in the tumor tissues. Lastly, pX rats described here appear to be suitable animal models for elucidating mechanisms involved in the tumorigenesis and the transactivation of the cellular genes by HTLV-I, especially by the pX gene products in vivo.
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PMID:[Pathological and molecular analyses of mammary tumors induced in HTLV-I pX transgenic rats]. 792 76

Marrow samples from 89 patients with aplastic anemia (AA) were evaluated for their ability to grow stromal layers in standard long-term marrow cultures (LTMCs). Results were highly variable: 6.8% failed to grow any stromal cells (group I); 42.5% either failed to grow to confluency or appeared to have a decreased number of adipocytes and/or macrophages (group II); and 52.8% appeared as normal confluent cultures with fibroblasts, adipocytes, and macrophages (group III). Analyses of patient data suggested that group I patients had a longer disease duration and poorer survival (P = .07). Enzyme-linked immunosorbent assay analysis of cytokine production was performed on 20 of the normal-appearing AA LTMCs and 12 LTMCs established from normal donors. Significant differences between the AA and control groups were apparent for macrophage inflammatory protein-1 alpha (MIP-1 alpha), interleukin-1 receptor antagonist (IL-1ra), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and leukemia-inhibitory factor (LIF). The most dramatic differences observed were elevated levels of MIP-1 alpha and GM-CSF and decreased levels of IL-1ra, particularly after IL-1 alpha stimulation. In contrast, IL-1 alpha stimulation of AA LTMCs produced levels of IL-6, LIF, and G-CSF comparable with those of controls. These data suggest that defects exist within the microenvironment of some AA marrows. Whether the majority of these defects are the cause or consequence of aplasia is not clear. However, we speculate that some of these abnormalities may contribute to the maintenance of the hypoplastic state and, in extreme cases, prevent engraftment of donor marrow.
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PMID:Aplastic anemia: analysis of stromal cell function in long-term marrow cultures. 794 23

Macrophage inflammatory protein-alpha (MIP-1 alpha), an 8-kDa peptide produced by stimulated macrophages, has been recently sequenced and cloned. In addition to its inflammatory effects, MIP-1 alpha inhibits proliferation of immature hematopoietic progenitors both in vitro and in vivo. Because the gene coding for MIP-1 alpha is expressed in peripheral blood cells obtained from patients with acute myelogenous leukemia (AML), we sought to evaluate the effect of MIP-1 alpha on AML precursors. We studied bone marrow samples from 21 AML patients using both the AML blast colony assay and the delta suspension culture assay. We found that recombinant human (rh) MIP-1 alpha significantly inhibits early and mature AML progenitors with sample-to-sample variability, by up to 79% at concentrations ranging from 40 to 1600 ng/ml. These results were obtained in the presence of fetal calf serum either alone or with granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, or interleukin-3. In contrast, rhMIP-1 alpha (400 ng/ml) did not significantly affect normal colony-forming unit granulocyte-macrophage (CFU-GM), or burst-forming unit-erythroid (BFU-E) proliferation. These data prompted us to delineate the inhibitory mechanism of MIP-1 alpha. Consequently, we used the thymidine suicide technique to measure DNA synthesis in AML progenitors and the enzyme-linked immunosorbent assay to quantify intracellular levels of interleukin-1 beta in AML blasts following incubation with MIP-1 alpha. We found that whereas MIP-1 alpha prevented AML progenitors from entering the proliferative phase of the cell cycle, it had no effect on interleukin-1 beta levels. Taken together, our data suggest that MIP-1 alpha may have clinical benefits in therapy for AML and should be considered for evaluation in a clinical setting.
Leukemia 1994 May
PMID:Inhibition of acute myelogenous leukemia progenitor proliferation by macrophage inflammatory protein 1-alpha. 818 37

We have examined basal and lipopolysaccharide (LPS)-induced release of epidermal growth factor (EGF), granulocyte-macrophage colony-stimulating factor (GM-CSF), growth-regulated peptide alpha (GRO alpha), leukaemia inhibitory factor (LIF), macrophage inflammatory protein-1a (MIP-1 alpha) and platelet-derived growth factor-AB (PDGF-AB) in peripheral blood mononuclear cells (PBMC) from 20 persons with either high (n = 10) or low (n = 10) levels of high-density lipoprotein (HDL). PBMC were incubated with 100 ng LPS/ml for up to 160 h, and showed a significantly higher release of the chemokines GRO alpha (P = 0.04) and MIP-1 alpha (P < 0.01) in persons with high HDL, whereas levels of GM-CSF were similar. Levels of EGF, LIF and PDGF-AB were always low, and remained unaltered during 160 h of incubation. These findings indicate that PBMC from persons with high or low levels of HDL have different functional properties, of importance in cell recruitment and activation.
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PMID:LPS-induced release of EGF, GM-CSF, GRO alpha, LIF, MIP-1 alpha and PDGF-AB in PBMC from persons with high or low levels of HDL lipoprotein. 858 Mar 73


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