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

Blood cell production is regulated by a complex interacting network of stem and progenitor cells, from which all the blood forming elements are derived, and the effects of cytokines which can up- or down-modulate proliferation or self-renewal of stem and progenitor cells (1,2). This report reviews in brief recent information on the characteristics of human umbilical cord blood progenitor cells, the effects of the potent co-stimulating molecule, steel factor, and the myelosuppressive effects of macrophage inflammatory protein 1 alpha and other members of this latter group of molecules termed cytokines. In vitro as well as preclinical and clinical in vivo effects are covered.
Leukemia 1992 Nov
PMID:Interactions of colony stimulating factors, other modulating cytokines and hematopoietic progenitor cells. Laboratory and clinical studies. 127 29

In previous studies on patients with juvenile chronic myelogenous leukaemia (JCML), we found excessive proliferation of malignant monocyte-macrophage elements in the absence of exogenous growth factor, and impaired growth of normal haematopoietic progenitors. In the current study, six newly-diagnosed JCML patients were investigated to characterize the disease further. In co-cultures, JCML cell culture supernatant as well as patient plasma obtained at diagnosis produced a striking reduction in numbers of control marrow BFU-E, CFU-GM, CFU-Meg and CFU-GEMM colonies. Monoclonal anti-tumour necrosis factor alpha neutralizing antibodies (anti-TNF-alpha Ab) abolished these inhibitory properties. In sharp contrast, JCML supernatants exerted a marked growth-promoting effect on autologous JCML cells cultured in clonogenic assays. Anti-TNF-alpha Ab and anti-granulocyte-macrophage colony-stimulating factor neutralizing antibodies (anti-GM-CSF Ab) both reversed the stimulating effect. Recombinant GM-CSF and recombinant TNF alpha produced a profound increase in JCML colonies when tested individually and anti-GM-CSF Ab reversed the TNF-alpha effect. Expression studies of TNF-alpha and TNF-alpha receptor genes of cultured JCML cells demonstrated mRNAs for both. Further, TNF-alpha activity was assayed in a wide variety of cell culture supernatants and in normal and patients' plasma, and only the JCML specimens showed increased TNF-alpha values. Recombinant interleukin-1 alpha (IL-1 alpha) also stimulated JCML colony growth, but polyclonal anti-IL-1 neutralizing antibodies did not suppress JCML colony numbers nor did it reverse the effects of TNF-alpha or GM-CSF. The evidence indicated that the JCML monokine which inhibits normal haematopoiesis is TNF-alpha and that the endogenously-produced TNF-alpha and GM-CSF from JCML cells play an important role in the pathogenesis of the disease by acting as autocrine growth factors. IL-1 alpha also stimulates JCML cell proliferation as an accessory factor and augments the effect of GM-CSF, TNF-alpha or both.
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PMID:Central role of tumour necrosis factor, GM-CSF, and interleukin 1 in the pathogenesis of juvenile chronic myelogenous leukaemia. 131 Nov 95

IL-1, IL-4, and IL-6 had no effect on hairy cell (HC) proliferation in vitro. Anti-mu and low molecular weight B cell growth factor (LBCGF) and tumor necrosis factor alpha (TNF-alpha) stimulated the proliferation of a minor subpopulation of HCs detected by double immunocytochemical staining. None of these cytokines had any effect on HC differentiation as measured by immunoglobulin secretion. It is concluded that none of the above growth factors are central to HC proliferation in-vivo. Since alpha-interferon IFN-alpha, but not IFN-gamma, consistently inhibited any proliferation observed, it seems likely that this monokine has a direct antiproliferative effect in vivo.
Leukemia 1990 May
PMID:The effect of cytokines, including IL-1, IL-4, and IL-6, in hairy cell proliferation/differentiation. 220 27

Establishment and total characterization of permanent growth-factor independent human leukemia cell lines are reviewed. Among others, a few significant contributions in the utility of leukemia cell lines described include establishment of immunodiagnosis of human leukemias and lymphomas, discovery of EB virus and of human retroviruses, proposed model of normal hematopoietic cell differentiation scheme, lymphokine-monokine production, identification and characterization, studies on genes responsible for immunobiological and growth regulatory molecules, and pharmacotoxicological and kinetic research. It is conceivable that the future leads by the utility of human leukemia cell lines to the advancement of research are indeed unlimited.
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PMID:Human leukemia cell lines--clinical and theoretical significances. 285 1

The effects of recombinant, macrophage-derived, murine tumor necrosis factor-alpha (TNF-alpha) on hematopoiesis in vivo has been examined in normal mice and in Friend virus (FV)-induced erythroleukemic mice. Intravenous (IV) administration of a single dose of recombinant murine TNF-alpha (10(5) U per mouse) significantly suppressed normal and leukemic late-stage erythropoiesis as measured by numbers of mature erythroid colony forming cells (CFU-E) in the bone marrow and spleen and by peripheral blood reticulocyte counts. In normal animals, the immature erythroid (BFU-E), macrophage (CFU-M), and granulocyte-macrophage (CFU-GM) compartments were significantly stimulated by TNF-alpha in both the bone marrow and the spleen. In the bone marrow of leukemic mice, the BFU-E, CFU-GM, and CFU-M progenitor cell compartments were also stimulated by treatment with the monokine. In the spleens of leukemic mice (the primary site of FV leukemia cell accumulation), relative numbers of BFU-E and CFU-GM were increased by TNF-alpha, while those of CFU-M were suppressed. TNF-alpha caused a rapid decrease in the markedly elevated spleen weights of progressively leukemic mice, and in multiple doses it caused complete clinical disease regression in a significant percentage of leukemic animals. The combination of TNF-alpha with interferon-gamma (IFN-gamma) increased the incidence of leukemia regression, compared with TNF-alpha alone. These results show that TNF-alpha exerts a suppressive influence on late-stage erythropoiesis in vivo and suggest that this effect might be exploited in the treatment of acute erythroleukemia, erythroid hyperplasias, and related diseases.
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PMID:In vivo hematopoietic effects of tumor necrosis factor-alpha in normal and erythroleukemic mice: characterization and therapeutic applications. 319 71

Leukemia cell lines of the monocytic series (HL-60, U-937, and P388D1) produce a hepatocyte-stimulating factor (HSF) following induction of differentiation with phorbol diester. In 24-72 hr, these leukemia cells produce 2-30% the amount of HSF as human peripheral blood monocytes. Cells of the series at earlier stages of differentiation produced greater amounts of HSF. Fractionation of the medium from each cell type by HPLC reveals much of the HSF activity in the 25- to 30-kilodalton range. Under the same culture conditions, interleukin 1 is produced; however, its bioactivity is in the 7- to 15-kilodalton range. Neither monokine shows reciprocal bioactivity. Superinducing culture conditions that greatly increase interleukin 1 production completely eliminate HSF production, suggesting that there is different stability of the mRNA coding for each protein or that there are different temporal events important to the induction of synthesis of these proteins.
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PMID:Identification and partial characterization of hepatocyte-stimulating factor from leukemia cell lines: comparison with interleukin 1. 388 60

Murine AIDS, induced by LP-BM5 murine leukemia retrovirus infection, causes a progressive and profound immunodeficiency in female C57B1/6 mice. Previously, we reported that autoantibodies were elevated during the initiation phases of this murine retrovirus infection and bound peptide determinants corresponding to CDR1 of several TCR V beta-chains. Therefore, we designed studies to determine whether administration of a major autoimmunogenic TCR V beta CDR1 peptide before or after infection with LP-BM5 retrovirus would modulate retrovirus-induced dysregulation of T cell function. Administration of the TCR V beta CDR1 peptide before murine retrovirus infection significantly prevented its suppression of splenic NK cell activity, T and B cell proliferation, and monokine (IL-6 and TNF-alpha) and Th1 cytokine (IL-2 and IFN-gamma) release by splenocytes, and inhibited retrovirus-induced elevation of Th2 cytokine (IL-5 and IL-10). Similar data were obtained with peptide immunization 2 wk after murine retrovirus infection at 6 and 16 wk postinfection. However, delaying peptide immunization until severe suppression of T and B cell mitogenesis had occurred did not restore their functions. Immunization with TCR V beta peptide prevents development of retrovirus-induced immune dysfunction, which suggests a possible pathogenic role of autoreactive T cells as regulatory elements.
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PMID:T cell receptor V beta complementarity-determining region 1 peptide administration moderates immune dysfunction and cytokine dysregulation induced by murine retrovirus infection. 763 74

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

Kinetics of circulating haematopoietic progenitors was analysed during chemotherapy- or chemotherapy plus granulocyte colony-stimulating factor (G-CSF)-induced mobilization of peripheral blood stem cells. Circulating progenitors including colony-forming unit granulocyte/macrophage (CFU-GM), burst forming-unit erythroid (BFU-E) and multilineage colony forming unit (CFU-Mix) were studied serially on alternate days during a recovery phase from chemotherapy for consolidation of complete remission. In 18 patients with acute leukaemia, 27 courses of consolidation chemotherapy were performed with a combination of an intermediate-dose cytosine arabinoside with etoposide (Ara-C/Etop) or mitoxantron (Ara-C/Mit). G-CSF (5 micrograms/kg) was administered during the recovery phase in 6/14 courses with Ara-C/Etop and in 4/13 courses with Ara-C/Mit. G-CSF induced a significant and synchronized increase of circulating CFU-GM, BFU-E and CFU-Mix by more than 4-fold at their peaks. The peak of CFU-GM was significantly correlated with that of both BFU-E and CFU-Mix, irrespective of additional G-CSF mobilization. G-CSF also produced a significant increase of monocytes in a synchronized fashion with an increase of circulating CFU-GM. Interestingly, peripheral blood monocytes spontaneously produced high concentrations of IL-6; a significant correlation was observed between absolute monocyte counts and plasma levels of IL-6 or peak levels of CFU-GM. These observations indicate that the addition of G-CSF to chemotherapy-induced mobilization can facilitate further expansion of a blood progenitor pool during the haematopoietic recovery, probably through the stimulation of monocytes to proliferate and to induce their monokine production such as IL-6. The data also suggest that absolute monocyte counts may be a useful indicator to predict the peak of circulating progenitors for collecting autologous blood stem cells.
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PMID:Kinetics of circulating haematopoietic progenitors during chemotherapy-induced mobilization with or without granulocyte colony-stimulating factor. 768 59

The effectiveness of endogenous or exogenously administered colony-stimulating factors may be modulated by the presence of hematopoietic inhibitory molecules. Cytotoxic therapy may result in the induction of hematopoietic inhibitors contributing to prolonged myelosuppression, whereas preventing the induction of such inhibitors may accelerate multilineage recovery. Lisofylline [LSF; (R)-1-(5-hydroxyhexyl)-3,7, dimethyl-xanthine], inhibits the signaling and/or release of certain hematopoietic inhibitory molecules such as tumor necrosis factor alpha, macrophage inflammatory protein 1 alpha, transforming growth factor beta, and IFN-gamma. Treatment of murine bone marrow cells with the cytotoxic agent 5-fluorouracil (5-FU) results in the release of a nondialyzable inhibitor of progenitor (colony-forming unit-granulocyte macrophage; CFU-GM) proliferation. When murine bone marrow cells were treated with 5-FU plus LSF, release of this inhibitor of CFU-GM proliferation was blocked. Neutralizing antibody and Western blot analysis indicated that the inhibitor was TGF-beta. We tested the effect of LSF (100 mg/kg i.p., b.i.d.) on multilineage regeneration after high-dose 5-FU or thiotepa treatment in BALB/c mice. In 4 of 5 experiments, LSF significantly accelerated neutrophil recovery (P < or = 0.05, Wilcoxon paired-signed test). In addition, platelet, reticulocyte, and CFU-GM regeneration were significantly accelerated in mice treated with LSF compared to control mice (P < or = 0.05). LSF had no significant effects on the ability of 5-FU to kill hematopoietic progenitor cells, nor did LSF stimulate or inhibit proliferation of CFU-GM. LSF had no effect on chemotherapy-induced killing of tumor cells in vitro, nor on the antitumor activity of 5-FU or thiotepa in BALB/c mice implanted with P388 leukemia cells. Inhibition of hematopoietic inhibitor release may accelerate multilineage recovery after cytotoxic therapy and, as such, may represent an alternative or additional therapy to the use of positively acting lineage specific colony-stimulating factors.
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PMID:Lisofylline inhibits transforming growth factor beta release and enhances trilineage hematopoietic recovery after 5-fluorouracil treatment in mice. 854 48


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