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)

To analyze the mechanisms by which cancer cells escape from hosts' immune surveillance, we investigated the changes in immune status during the progression of leukemia induced by injecting mice with WEHI-3B cells. In the bone marrow (BM) of leukemic mice, only DX5(+)CD3(-) cells were continuously increased, despite the progression of leukemia. In addition, DX5(+)CD3(-) cells were rapidly increased in peripheral blood (PB) 20 days after inoculation. We also found that myeloid dendritic cells (DCs) expressing low levels of I-A(d) and having low allo-T cell stimulatory activity were markedly increased in PB and spleen. The increase in DX5(+) cells in BM was thought to be induced by soluble factors from leukemic cells. DX5(+) cells from leukemic mice were CD3(-), B220(-), Gr-1(-), CD14(-), CD94(-), Ly-49C/F(-), asialo GM1(+), CD25(+), CD122(+), Thy-1(bright), and c-kit(dim) and showed low killing activity against YAC-1 cells, suggesting that those DX5(+) cells were immature NK cells. NK cells from leukemic PB down-regulated the expression of I-A(d) on DCs, an effect mediated by TGF-beta. Moreover, these NK cells significantly suppressed the allo-T cell stimulatory activity of DCs, an effect requiring cell-to-cell contact between NK cells and DCs and thought to involve CD25. Importantly, NK cells from leukemic PB inhibited generation of autotumor-specific CTL induced by DCs in primary MLR or by DC immunization. In conclusion, we identified circulating immature NK cells with immunosuppressive activities. These cells may be important for understanding the involvement of the host immune system during the development of leukemia.
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PMID:Immature NK cells suppress dendritic cell functions during the development of leukemia in a mouse model. 1654 47

CD4(+)CD25(+) regulatory T cells have been characterized as a critical population of immunosuppressive cells. They play a crucial role in cancer progression by inhibiting the effector function of CD4(+) or CD8(+) T lymphocytes. However, whether regulatory T lymphocytes that expand during tumor progression can modulate dendritic cell function is unclear. To address this issue, we have evaluated the inhibitory potential of CD4(+)CD25(+) regulatory T cells from mice bearing a BCR-ABL(+) leukemia on bone marrow-derived dendritic cells. We present data demonstrating that CD4(+)CD25(+)FoxP3(+) regulatory T cells from tumor-bearing animals impede dendritic cell function by down-regulating the activation of the transcription factor NF-kappaB. The expression of the co-stimulatory molecules CD80, CD86 and CD40, the production of TNF-alpha, IL-12, and CCL5/RANTES by the suppressed DC is strongly down-regulated. The suppression mechanism requires TGF-beta and IL-10 and is associated with induction of the Smad signaling pathway and activation of the STAT3 transcription factor.
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PMID:Tumor-derived CD4(+)CD25(+) regulatory T cell suppression of dendritic cell function involves TGF-beta and IL-10. 1661 96

Cotylenin A, which has been isolated as a plant growth regulator, potently induces the differentiation of human myeloid leukemia cells. Treatment of HL-60 cells with a combination of transforming growth factor (TGF)-beta and 1alpha, 25-dihydroxyvitamin D(3) (VD3) resulted in increased differentiation compared to separate treatments, but TGF-beta did not affect the cotylenin A-induced differentiation of HL-60 cells. It is possible that the signal transduction pathway used by cotylenin A for inducing the differentiation of leukemia cells is the same as that used by TGF-beta. However, cotylenin A did not affect the expression of TGF superfamily or Smad genes in HL-60 cells. Treatment with neutralizing anti-TGF-beta antibody or an inhibitor of TGF-beta signaling did not inhibit cotylenin A-induced differentiation, although VD3-induced differentiation was significantly suppressed by these treatments. The subcellular distribution of Smad3 was also unaffected by cotylenin A. These results suggest that the cotylenin A-induced differentiation of leukemia cells is independent of the TGF-beta signaling system, although TGF-beta acts as an autocrine mediator of the growth arrest and differentiation of leukemia cells induced by VD3 and other inducers.
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PMID:Cotylenin A-induced differentiation is independent of the transforming growth factor-beta signaling system in human myeloid leukemia HL-60 cells. 1669 May 33

The role of angiogenesis in solid tumours is well recognised, but its importance in haematological malignancies is less well understood. In leukaemia, mainly the determination of microvascular density utilising immunohistochemistry in the bone marrow trephines and the measurement of soluble angiogenic factors have led to the recognition that angiogenesis may be important in leukaemia as well. In this study, the soluble form of the endothelial cell activation/proliferation (i.e., angiogenesis) marker CD105 and its ligands TGFbeta-1 and -3, as well as the ligand/receptor complexes in plasma from children with acute lymphoblastic leukaemia (ALL) were quantified. The plasma level of CD105 was significantly higher in patients with common ALL compared to controls, while the TGFbeta-3 level was lower in patients. Neither the CD105 or TGFbeta-3 levels were of prognostic value, nor did they correlate with any of the known prognostic indicators, such as white blood cell counts. There were no significant differences between the plasma levels of any of the other parameters, such as TGFbeta-1 or the ligand receptor complexes, in children with leukaemia compared to controls. Our results support the role of angiogenesis in leukaemia and suggest that anti-angiogenesis may be a therapeutic target in leukaemia.
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PMID:Plasma CD105, TGFbeta-1, TGFbeta-3 and the ligand/receptor complexes in children with acute lymphoblastic leukaemia. 1673 17

T-cell subpopulations, defined by their expression of CD4, CD8, naive, and memory cell-surface markers, occupy distinct homeostatic compartments that are regulated primarily by cytokines. CD8+ memory T cells, as defined by CD44(hi) surface expression, are dependent on IL-15 as a positive regulator of their homeostatic maintenance. Manipulation of IL-15 signaling through gene aberration, overexpression, or receptor alterations has been shown to dramatically affect T-cell homeostasis, with overexpression leading to fatal leukemia. Here we show that TGF-beta is the critical negative regulator of murine CD8+ memory T-cell homeostasis with direct opposition to the positive effects of IL-15. This negative regulation is mediated, at least in part, by the ability of TGF-beta to modulate expression of the beta-chain of the IL-15 receptor, thus establishing a central axis between these 2 cytokines for homeostatic control of CD8+ memory T-cell populations. These data establish TGF-beta as a critical and dominant tumor-suppressor pathway opposing IL-15-mediated CD8+ T-cell expansion and potential malignant transformation.
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PMID:Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice. 1678 95

Loss of transforming growth factor (TGF)-beta signaling has been implicated in malignant transformation of various tissues. Smad4 plays a central role in the signal transduction of TGF-beta. Deletion or mutation of Smad4 has been described in a number of cancers. This study was aimed to investigate a potential role of Smad4 in leukemia including its expression and location in blast cells. The mononuclear cells were separated from bone marrow of leukemia patients. The samples, blast cells of which were more than 90% in mononuclear cells, were selected. The expression and location of Smad4 protein were analyzed by immunohistochemistry methods. The results showed that the Smad4 protein located mainly in nucleus, part of this protein located in cytoplasma, the expressions of Smad4 were not detected in 6 out of 9 ALL patients, in 7 out of 24 AML patients and in 1 out of 2 CML patients; these leukemia patients, in whose cells the expression of Smad4 was not detected, included one L1 and one L3, four L2, one M0, one M1, two M2a, one M3a, one M4b, one M6 and one CML. In conclusion, the Smad4 protein was mainly in nucleus, the deletion or functional change of Smad4 may related with the pathogenesis of human AML.
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PMID:[Expression of Smad4 in leukemia cells]. 1692 97

Natural killer (NK) cells play an important role in tumor-cell clearance, particularly against leukemia, as shown by killer cell inhibitory receptor (KIR)-mismatched allogeneic stem cell transplantation. Analysis of in vitro IL-2-expanded NK cells from patients with myelocytic/monocytic acute myeloid leukemia (AML-NK cells) has revealed poor cytolytic functions because of deficient expression of pivotal activation molecules-the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. To exclude the possibility that this observation was caused by the in vitro amplification of a small NCR(dull) population, we analyzed the AML-NK phenotype directly, without any in vitro expansion. We first confirmed that the NCR(dull) phenotype was not an in vitro artifact. Moreover, analysis of a large population of AML patients allowed us to demonstrate that phenotype was not restricted to a French-American-British (FAB) subtype and was not associated with a particular cytogenetic abnormality. Our longitudinal study of AML patients showed that the NCR(dull) phenotype was acquired during leukemia development because we observed its complete (for NKp46) or partial (for NKp30) reversibility in patients achieving complete remission (CR). Reversibility of the NCR(dull) phenotype after CR suggested that leukemia cells might be involved in NCR down-regulation. In agreement with this hypothesis, direct contact between leukemic blasts and NK cells (but not leukemia-cell supernatants) induced loss or decrease in NKp30 and NKp46 expression while impeding NKp44 induction by IL-2. We excluded the major implication of TGF-beta in NCR down-regulation. Although the clinical antitumor value of NK cells is clearly demonstrated in allogeneic stem cell transplantation, the role of NK cells in autologous transplantation is not proved. Interestingly, we observed a correlation between the NCR(dull) phenotype and poor survival in AML patients, suggesting that NK-deficient activation caused by NCR down-regulation could play a role in patient outcome. The prognostic value of NCR expression is discussed, and pathophysiologic implication of the NCR phenotype will be further investigated in a larger study.
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PMID:Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. 1694 Apr 27

Pathological angiogenesis is increasingly recognized to be an important feature of pathogenesis in solid tumors and also in leukemias. Specific blockers of angiogenesis are now being introduced into early clinical trials with encouraging results. Vascular endothelial growth factor (VEGF) seems to play a central role in tumor angiogenesis and is associated with a poor prognosis in both solid tumors and adult leukemias. In pediatric acute lymphocytic leukemia however, the expression of angiogenic molecules and its relation to prognosis and relapse are unknown. Therefore, we prospectively analyzed 46 pediatric patients with precursor B cell acute lymphocytic leukemia by semi-quantitative RT-PCR for expression of the angiogenic molecules VEGF, VEGF-C, iNOS and TGF-beta and correlated relapse and survival data with the expression of these factors. We found a high mRNA expression of TGF-beta and iNOS, a moderate expression of VEGF but no expression of bFGF and VEGF-C. A significantly higher expression of VEGF mRNA was found in patients with late relapses compared to patients without relapses (p=0.043). A significantly higher mRNA expression of iNOS was found in surviving patients compared with non-surviving patients (p=0.023). Angiogenic factors are expressed in the bone marrow of patients with pediatric B cell precursor ALL and VEGF is a potential candidate for therapeutic intervention as it is significantly higher expressed in children with late relapses. The mRNA expression of iNOS in the surviving children possibly reflects an increased activity of the immune system against the leukemia which leads to a superior survival.
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PMID:Expression of angiogenic factors in childhood B-cell precursor acute lymphoblastic leukemia. 1714 92

The Tax oncoprotein of human T-cell leukaemia virus type I (HTLV-I) persistently activates nuclear factor-kappaB (NF-kappaB), which is required for HTLV-I-mediated T-cell transformation. Tax activates NF-kappaB by stimulating the activity of IkappaB kinase (IKK), but the underlying mechanism remains elusive. Here, we show that Tax functions as an intracellular stimulator of an IKK-activating kinase, Tak1 (TGF-beta-activating kinase 1). In addition, Tax physically interacts with Tak1 and mediates the recruitment of IKK to Tak1. In HTLV-I-infected T cells, Tak1 is constitutively activated and complexed with both Tax and IKK. We provide genetic evidence that Tak1 is essential for Tax-induced IKK activation. Furthermore, unlike cellular stimuli, the Tax-specific NF-kappaB signalling does not require the ubiquitin-binding function of IKKgamma. These findings show a pathological mechanism of IKK activation by Tax and provide an example for how IKK is persistently activated in cancer cells.
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PMID:Retroviral oncoprotein Tax deregulates NF-kappaB by activating Tak1 and mediating the physical association of Tak1-IKK. 1736 73

Atiprimod (Atip) is a novel oral agent with anti-inflammatory properties. Although its in vitro activity and effects on signaling in multiple myeloma (MM) have been previously reported, here we investigated its molecular and in vivo effects in MM. Gene expression analysis of MM cells identified downregulation of genes involved in adhesion, cell-signaling, cell cycle and bone morphogenetic protein (BMP) pathways and upregulation of genes implicated in apoptosis and bone development, following Atip treatment. The pathway analysis identified integrin, TGF-beta and FGF signaling as well as Wnt/beta-catenin, IGF1 and cell-cycle regulation networks as being most modulated by Atip treatment. We further evaluated its in vivo activity in three mouse models. The subcutaneous model confirmed its in vivo activity and established its dose; the SCID-hu model using INA-6 cells, confirmed its ability to overcome the protective effects of BM milieu; and the SCID-hu model using primary MM cells reconfirmed its activity in a model closest to human disease. Finally, we observed reduced number of osteoclasts and modulation of genes related to BMP pathways. Taken together, these data demonstrate the in vitro and in vivo antitumor activity of Atip, delineate potential molecular targets triggered by this agent, and provide a preclinical rational for its clinical evaluation in MM.
Leukemia 2007 Dec
PMID:Biological pathways and in vivo antitumor activity induced by Atiprimod in myeloma. 1788 85


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