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

Chronic lymphocytic leukemia (CLL) is the most common leukemia of the western world and is characterized by a slowly progressing accumulation of clonal CD5+ B cells. Our laboratory has investigated the role of transforming growth factor-beta (TGF-beta) and interleukin-4 (IL-4) in the pathogenesis of B-cell expansion in CLL. In vitro addition of TGF-beta did not increase spontaneous apoptosis of B cells from most CLL patients, as determined using the TUNEL method, compared with a twofold increase observed in cultures of normal B cells. There was similar expression of TGF-beta type II receptors on both CLL B cells and normal B cells. In contrast to apoptosis, CLL B-cell proliferation was variably inhibited with addition of TGF-beta. In vitro addition of IL-4, previously reported to promote CLL B-cell survival, dramatically reduced spontaneous apoptosis of CLL B cells compared with normal B cells. CLL B-cell expression of IL-4 receptors was increased compared to normal B cells. Thus, our results show aberrant apoptotic responses of CLL B cells to TGF-beta and IL-4, perhaps contributing to the relative expansion of the neoplastic clone.
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PMID:Chronic lymphocytic leukemia B cells are resistant to the apoptotic effects of transforming growth factor-beta. 902 25

This review considers the potential reduction of embryo mortality in vitro and in vivo in ruminants. Data on cytokines provided by different fields of reproductive immunology and biology were collated. Because of the crucial importance of the local interactions between the embryo and its dam, the expression of growth-factor and cytokine genes was analysed in the embryo proper, trophoblast, oviduct and endometrium by reverse transcriptase polymerase chain reaction in sheep and in cattle during the pre- and periimplantation periods. Many deleterious cytokines, such as tumour necrosis factor-alpha, interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and beneficial cytokines, such as transforming growth factor-beta, leukaemia inhibiting factor, colony-stimulating factor-1 (CSF-1), granulocyte-macrophage CSF, IL-1, IL-3, IL-4, IL-6, IL-10 and IFN-tau appeared to be involved in embryo survival in ruminants and other species. Their administration is efficient in a murine experimental model (CBA/J x DBA/2) of embryonic and fetal mortality. For instance, recombinant ovine IFN-tau (roIFN-tau) injected at the moment of implantation drastically reduces embryonic mortality in this model. In ruminants, roIFN-tau and recombinant bovine IFN-tau are very efficient in maintaining progesterone luteal secretion in cyclic animals. The involvement of IFN-tau in the mechanisms of maternal pregnancy recognition are particularly detailed in relation to inhibition of 13,14 dihydro-15-keto-prostaglandin F2 alpha (PGFM) pulses and oxytocin uterine receptivity. A synthetic model of the anti-luteolytic effects of IFN-tau on the endometrial cell is proposed. Finally, the particular potential of serum pregnancy-specific proteins (PSPs: PSPB, PSP60, pregnancy-associated glycoprotein) for monitoring embryo survival, with examples given for cattle and sheep is underlined.
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PMID:Recent developments and potentialities for reducing embryo mortality in ruminants: the role of IFN-tau and other cytokines in early pregnancy. 926 83

We have previously shown that allospecific murine CD8+ T cells of the Tc1 and Tc2 phenotype could be generated in vitro, and that such functionally defined T-cell subsets mediated a graft-versus-leukemia (GVL) effect with reduced graft-versus-host disease (GVHD). To evaluate whether analogous Tc1 and Tc2 subsets might be generated in humans, CD8+ T cells were allostimulated in the presence of either interleukin-12 (IL-12) and transforming growth factor-beta (TGF-beta) (Tc1 culture) or IL-4 (Tc2 culture). Tc1-type CD8 cells secreted the type I cytokines IL-2 and interferon gamma (IFN-gamma), whereas Tc2-type cells primarily secreted the type II cytokines IL-4, IL-5, and IL-10. Both cytokine-secreting populations effectively lysed tumor targets when stimulated with anti-T-cell receptor (TCR) antibody; allospecificity of Tc1- and Tc2-mediated cytolytic function was demonstrated using bone marrow-derived stimulator cells as targets. In addition, both Tc1 and Tc2 subsets were capable of mediating cytolysis through the fas pathway. We therefore conclude that allospecific human CD8+ T cells of Tc1 and Tc2 phenotype can be generated in vitro, and that these T-cell populations may be important for the mediation and regulation of allogeneic transplantation responses.
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PMID:In vitro generation of allospecific human CD8+ T cells of Tc1 and Tc2 phenotype. 929 48

The t(3;21)(q26;q22) chromosomal translocation associated with blastic crisis of chronic myelogenous leukemia results in the formation of the AML1/Evi-1 chimeric protein, which is thought to play a causative role in leukemic transformation of hematopoietic cells. Here we show that AML1/Evi-1 represses growth-inhibitory signaling by transforming growth factor-beta (TGF-beta) in 32Dcl3 myeloid cells. The activity of AML1/Evi-1 to repress TGF-beta signaling depends on the two separate regions of the Evi-1 portion, one of which is the first zinc finger domain. AML1/Evi-1 interacts with Smad3, an intracellular mediator of TGF-beta signaling, through the first zinc finger domain, and represses the Smad3 activity, as Evi-1 does. We also show that suppression of endogenous Evi-1 in leukemic cells carrying inv(3) restores TGF-beta responsiveness. Taken together, AML1/Evi-1 acts as an inhibitor of TGF-beta signaling by interfering with Smad3 through the Evi-1 portion, and both AML1/Evi-1 and Evi-1 repress TGF-beta-mediated growth suppression in hematopoietic cells. Thus, AML1/Evi-1 may contribute to leukemogenesis by specifically blocking growth-inhibitory signaling of TGF-beta in the t(3;21) leukemia.
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PMID:The t(3;21) fusion product, AML1/Evi-1, interacts with Smad3 and blocks transforming growth factor-beta-mediated growth inhibition of myeloid cells. 983 2

The aim of this study was to identify and characterize binding sites for inhibin in primary cultures of ovine anterior pituitary cells. Recombinant human 31-kDa inhibin A was iodinated by an optimized lactoperoxidase procedure. Fractionation of the labeled protein by gel filtration chromatography on Sephadex G-100 in 0.1 M HCl yielded two immunoactive peak regions, the second of which was bioactive as assessed by in vitro bioassay, with a ratio of bioactivity/immunoactivity of 0.62-0.77 and an iodine incorporation ratio of 1.7-2.0 mol 125I/mol inhibin. The specific binding of purified [125I]inhibin to cultured ovine pituitary cells varied with time, temperature, and cell number. Displacement of the tracer by unlabeled inhibin, as assessed by Scatchard analysis, revealed two binding sites with average Kd values of 0.28 and 3.9 nM and with approximately 250 and 3100 binding sites/anterior pituitary cell, respectively. There was little cross-reaction between inhibin and activin A (<2%), transforming growth factor-beta (<0.2%), or follistatin (<<0.1%). Examination of cell lines that were not expected to have inhibin receptors showed that there was no specific binding of inhibin to human leukemia (Jurkat) cells, whereas the binding to human embryonic kidney (293) cells was displaced by both inhibin and activin with a similar degree of cross-reaction, which suggests binding to an activin receptor. It is concluded that inhibin-binding sites with high affinity and specificity have been identified on ovine pituitary cells, consistent with both inhibin action on the pituitary and the presence of the putative inhibin receptor.
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PMID:Identification of high affinity binding sites for inhibin on ovine pituitary cells in culture. 988 99

Genomic instability is one mechanism proposed to play a role in the disease progression of chronic myeloid leukemia (CML). Microsatellite regions in the type II transforming growth factor-beta receptor (TGF-beta RII) gene appear to be targets for mutation in some cancers displaying microsatellite instability (replication error phenotype, RER+). Furthermore, TGF-beta RII mutations in RER+ tumors have been associated with decreased TGF-beta RII mRNA levels. As TGF-beta is a potent negative growth regulator of hematopoietic cells, investigations were undertaken to determine whether inactivation of the receptor by microsatellite alteration might be involved in the progression of CML. Analysis of TGF-beta RII mRNA expression by RNase protection, with comparison of cells from the chronic, accelerated and blast phases of CML, showed no change in TGF-beta RII transcript levels during disease progression. However, during each phase of the disease, low levels of TGF-beta RII were detected when compared with the hematopoietic cells of normal donors. Furthermore, this decreased expression was also observed in the other myeloproliferative disorders, polycythemia rubra vera (PRV) and essential thrombocythemia (ET). The leukemia cell lines K562 and HL-60 had no detectable TGF-beta RII mRNA. Two microsatellite regions found altered in RER+ colon cancers were analyzed to establish if these sequences were aberrant in CML. No alteration was detected in either of these regions in any phase of the disease. These results suggest that alterations of the microsatellite regions in the TGF-beta RII gene are not involved in the progression of CML. Decreased expression of TGF-beta RII in CML cells and leukemia cell lines raises the possibility that altered expression of the receptor may play a role in the initiation and/or maintenance of the disease state.
Leukemia 1999 Apr
PMID:The TGF-beta type II receptor in chronic myeloid leukemia: analysis of microsatellite regions and gene expression. 1021 59

Important functional differences exist between primitive CD34++ CD38- hematopoietic progenitor cells derived from human fetal liver (FL) and adult bone marrow (ABM). FL progenitors are known to have higher proliferative capacities and lower cytokine requirements than their ABM counterparts. In this study, we isolated FL and ABM CD34++ CD38- cells and used a two-stage culture system to investigate the effects of transforming growth factor-beta (TGF-beta) and blocking anti-TGF-beta antibodies (anti-TGF-beta) on these cells. First, we demonstrate that FL progenitors are significantly less sensitive to the inhibitory effects of TGF-beta than ABM cells. Second, whereas ABM cells are significantly stimulated by anti-TGF-beta, only very limited effects are seen on FL cells. Third, we show that the effect of anti-TGF-beta is mainly situated at the level of the initial cell cycles of very primitive progenitor cells with a high proliferation potential. Fourth, we demonstrate that blocking the effects of endogenous TGF-beta reduces the growth factor requirements of ABM cells in order to proliferate and differentiate. Based on these data, we hypothesize that at least part of the functional differences that exist between adult and fetal stem cells can be accounted for by a developmental different responsiveness to TGF-beta.
Leukemia 1999 Aug
PMID:Developmentally regulated responsiveness to transforming growth factor-beta is correlated with functional differences between human adult and fetal primitive hematopoietic progenitor cells. 1045 Jul 56

To identify potential roles of cytokines in retroviral pathogenesis, we used reverse transcription-quantitative competitive polymerase chain reaction (RT-qcPCR) assays to characterize mRNA levels of 19 different lymphokines, chemokines, monokines and hematopoietic growth factors in three feline cell lines productively infected with subgroup A feline leukemia virus (FeLV-A) or various feline immunodeficiency virus (FIV) strains. Infection of a CD8+, CD5- large granular lymphocyte (LGL) cell line with FeLV-A activated expression of interleukin-7 (IL-7), induced modest (4-fold) increases in granulocyte/macrophage colony-stimulating factor (GM-CSF) and leukemia inhibitory factor (LIF) transcripts, and decreased transforming growth factor-beta (TGF-beta) mRNA (4-fold). The LGL cells were not susceptible to infection by FIV. Infection of MYA-1 cells, a CD4+ T-lymphoblastoid cell line, with FeLV-A activated expression of macrophage inflammatory protein-1alpha (MIP-1alpha), increased transcript levels of GM-CSF (8-fold), macrophage CSF (M-CSF) (16-fold) and stem cell factor (SCF) (250-fold), and decreased (4-fold) expression of IL-10 and tumor necrosis factor-alpha (TNF-alpha). Productive infection with four different FIV molecular clones caused progressive MYA-1 cell death; however, the mRNA expression profiles were unchanged except for 2- to 4-fold increases in M-CSF and 16- to 500-fold increases in SCF. Thus, FIV-induced MYA-1 cytopathicity was not associated with dysregulation of pro-apoptotic or survival factor transcript levels. Lastly, productive infection of PNI cells, a marrow-derived fibroendothelial cell line, with FeLV-A or any of three FIV strains induced 4-fold higher levels of IL-12p40 transcripts and variably higher levels (4- to 64-fold) of GM-CSF. Two viral strains, the FIV-14 molecular clone and the clinical isolate FIV-5122, caused syncytia formation and unique activation of IL-1beta and stromal cell-derived factor-1 (SDF-1) expression, suggesting a potential role for those factors in viral spread and/or cytopathicity. In addition, infection with FIV-5122, but not the other FIV strains or FeLV-A, induced significant increases in mRNA levels of the hematopoietic inhibitors TNF-alpha and MIP-1alpha, along with increased concentrations of soluble proteins in culture supernatants. Consistent with this, supernatant from FIV-5122 infected PNI cells suppressed hematopoietic progenitor growth in colony assays, compared to supportive activities in supernatants from other infected or uninfected PNI cell cultures. Together, these data demonstrate that feline retroviruses alter cytokine mRNA levels in general and strain-specific patterns. These changes may result in specific alterations in cell function and contribute to retroviral pathogenesis. Our observations provide a basis for directed studies of candidate factors within the hematopoietic, thymic and lymphoid microenvironments.
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PMID:The effects of feline retroviruses on cytokine expression. 1062 77

Neurotrophic factors are known to play a crucial role in the elongation and guidance of auditory nerve fibres to their targets within the organ of Corti. Maintenance of these neural connections following deafness would clearly influence the efficacy of therapies for hearing recovery. The growth factors leukaemia inhibitory factor (LIF), brain-derived neurotrophic factor (BDNF) and transforming growth factor-beta 5 (TGF-beta5) were tested for their efficacy in promoting neurite outgrowth from dissociated cultures of early postnatal rat auditory neurons. Our results indicate that while BDNF enhances neurite outgrowth in a strong fashion, LIF is more potent; moreover, the combined administration of both factors has even greater neuritogenic capacities. TGF-beta5, although neurotrophic, has no neuritogenic activity on cultured auditory neurons. LIF and BDNF may therefore be potential candidates when developing pharmacological therapies for hearing recovery.
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PMID:LIF is more potent than BDNF in promoting neurite outgrowth of mammalian auditory neurons in vitro. 1120 34

In 58 patients with mast cell disease (MCD) and three with basophilic leukemia, bone marrow (54 cases) or skin tissue (four cases) was studied immunohistochemically for expression of Kit (c-kit protein), the different isomers of transforming growth factor-beta (TGF-beta), basic fibroblast growth factor (bFGF), and their respective receptors. Kit was expressed in all cases of MCD but in none of basophilic leukemia. Expression pattern of cytokines and their receptors was variable in systemic MCD with (SMCD-HD) or without (SMCD) associated hematologic disorder. However, type I TGF-beta receptor (TGFbeta1R) was not expressed in 30% of SMCD-HD patients or in patients with mast cell leukemia, but the remaining cases of MCD showed near uniform expression. The associated hematologic disorders in TGFbeta1R-negative cases of SMCD-HD were prognostically less favorable than those associated with TGFbeta1R-positive cases of SMCD-HD. The results confirm the diagnostic value of Kit immunohistochemistry in MCD and suggest a biologically relevant heterogeneity in TGFbeta1R expression among patients with SMCD-HD.
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PMID:Immunohistochemical studies of c-kit, transforming growth factor-beta, and basic fibroblast growth factor in mast cell disease. 1173 6


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