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)

A pregnancy rate of approximately 15% per cycle renders the process of human reproduction inefficient. The cycle-dependent expression of molecules involved in the embryo-endometrial dialogue has lead to the identification of a 'window of implantation'. This is the unique temporal and spatial expression of factors that allows the embryo to implant (via signalling, appositioning, attachment and invasion) in a specific time frame of 48 h, 7-10 days after ovulation. Integrin molecules, L-selectin ligands, mucin-1, heparin-binding epidermal growth factor and pinopodes are involved in appositioning and attachment. The embryo produces cytokines and growth factors [interleukins, prostaglandins, vascular endothelial growth factor (VEGF)] and receptors for endometrial signals (leukaemia inhibitory factor receptor, colony stimulating factor receptor, insulin-like growth factors and heparin binding epidermal growth factor receptor). The immune system plays an important role. Immunomodulatory factors such as glycodelin, inhibin and interleukin prevent a graft-versus-host reaction. Angiogenesis controlled by VEGF and prostaglandins is needed for formation of a receptive endometrium and a placenta. Identification of these factors has led to their use as markers of implantation that may identify defects causing subfertility. An ideal marker of implantation is sensitive and specific, and easy to obtain without disturbing implantation. Glycodelin and leukaemia inhibitory factor (serum) and integrins and pinopodes (biopsies) are promising candidates.
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PMID:Human embryo implantation: current knowledge and clinical implications in assisted reproductive technology. 1567 Apr 21

Post-translational modification of Bcl-2 protein has been described in a variety of cell models with effects varying from enhanced to abrogated function. In this study, we demonstrated that Bcl-2 was constitutively phosphorylated in several hematopoietic tumor cell lines and in primary ALL cells. Increased phosphorylation of Bcl-2 protein in the JM1 ALL cell line, achieved by expression of the phosphomimetic Bcl-2 construct S70E, enhanced JM1 cell chemoresistance. In contrast, initiation of JM1 cell apoptosis was coincident with dephosphorylation of Bcl-2 and elevated protein phosphatase 2A activity. S70E expression also diminished tBid-mediated cytochrome c release and blunted chemotherapy-induced activation of caspases-9 and -3 in JM1 cells. To determine whether soluble factors produced by stromal cells in the bone marrow influence phosphorylation of Bcl-2 protein, a panel of recombinant cytokines was evaluated. Of those tested, vascular endothelial growth factor (VEGF) induced phosphorylation of Bcl-2 protein and blunted cytochrome c release during chemotherapy or tBid treatment of ALL cells. In contrast, JM1 cells transfected with S70A, resulting in expression of Bcl-2 protein that cannot be phosphorylated, were not efficiently rescued from apoptosis by VEGF. These observations suggest that optimal protection of leukemic cells by VEGF may require activation of a pathway that includes Bcl-2 phosphorylation.
Leukemia 2005 Mar
PMID:VEGF-induced phosphorylation of Bcl-2 influences B lineage leukemic cell response to apoptotic stimuli. 1569 71

The stromal compartments of hematopoietic organs (eg, spleen) are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend murine leukemia virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared with age-matched sham controls. In vitro, the proliferation of primary erythroleukemic cells cocultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in cocultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), macrophage chemoattractant protein-5 (MCP-5), soluble tumor necrosis factor receptor-1 (sTNFR1), IL-12p70, tumor necrosis factor-alpha (TNF-alpha), and IL-2 over normal splenocytes. Medium supplemented with both VEGF-A and MCP-5 could sustain proliferation of primary erythroleukemic cells in vitro, and significant proliferative suppression was observed upon addition of neutralizing antibodies to either of these factors. Furthermore, in vivo administration of a neutralizing antibody to VEGF-A extended survival times of erythroleukemic mice in comparison with controls. These findings suggest that VEGF-A and MCP-5 are potentially pivotal paracrine mediators occurring within the diseased splenic microenvironment capable of promoting disease acceleration and expansion of erythroleukemic blasts.
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PMID:The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells. 1570 19

We have previously shown that chronic lymphocytic leukemia (CLL) B cells secrete vascular endothelial growth factor (VEGF) in vitro, have constitutively active VEGF receptors R1 and R2, and respond to exogenous VEGF by specifically upregulating Mcl-1 and XIAP in association with decreased cell death. We found that epigallocatechin (EGCG) decreases VEGF receptor phosphorylation and induces apoptosis in CLL B cells. The mechanism(s) by which VEGF receptor activation increases Mcl-1 and XIAP and promotes survival remains unknown. To further define the signaling pathway mediating VEGF induction of antiapoptotic proteins in CLL B-cells, we investigated downstream effects of VEGF-VEGF receptor binding on the STAT signaling pathway. We find that CLL B cells abundantly express cytoplasmic serine phosphorylated (p)-STAT-1 and p-STAT-3, VEGF-R1/2 are physically associated with p-STAT-1 and p-STAT-3, and p-STAT-3 (but not p-STAT-1) is found in the CLL nucleus. VEGF receptor ligation selectively induces activation and perinuclear translocation of STAT 3 through receptor-mediated endocytosis. The inhibition of VEGF receptor activation with either tyrosine kinase inhibitors or VEGF neutralizing antibodies inhibit VEGF receptor phosphorylation, decrease p-STAT-3 (serine 727), Mcl-1, and induces cell death in CLL B cells. Thus, a VEGF-VEGF receptor pathway in CLL B cells can be linked to activation of STAT proteins that are able to enhance their apoptotic resistance.
Leukemia 2005 Apr
PMID:VEGF receptors on chronic lymphocytic leukemia (CLL) B cells interact with STAT 1 and 3: implication for apoptosis resistance. 2038 4

Leptin alone and in combination with other cytokines has a stimulatory effect on proliferation of leukaemic cells. This effect may be due to prevention of apoptosis of progenitor cells or upregulation of specific receptors on leukaemic precursors that make them more responsive to stimuli. This work investigates the relationship between serum leptin level, serum interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in acute leukaemic patients. The relationship to blood cell counts, haemoglobin and response to chemotherapy was also investigated. The study included 25 acute leukaemic male patients [15 acute myeloid leukaemia (AML) and 10 acute lymphoblastic leukaemia (ALL)] and 15 age and sex matched healthy controls. All were subjected to thorough history taking, clinical examination, complete blood picture, hepatic and renal function tests and determination of serum leptin, IL-6 and VEGF levels. In addition, patients were subjected to bone marrow aspiration, cytochemistry and immunophenotyping study and serum leptin assay after chemotherapy. Serum leptin level showed statistically significant elevation only in AML group (p<0.01). This elevation was unrelated to the presence of extramedullary infiltration or response to chemotherapy and correlated only with body mass index (p<0.05). In ALL, the mean serum leptin level was insignificantly different from the controls. In both AML and ALL, there was no significant difference in serum leptin level before and after treatment. Statistically significant elevation of IL-6 and VEGF, uncorrelated with serum leptin level was detected in AML patients when compared with the controls. No correlation was found between serum leptin level and any of the studied haematological parameters. It is concluded that the release of leptin, IL-6 and VEGF may be regulated by different mechanisms leading to diversity in clinical features of the disease.
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PMID:Leptin in acute leukaemias: relationship to interleukin-6 and vascular endothelial growth factor. 1571 23

The study was to investigate the expression levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the serum of patients with acute leukemia and supernatants of leukemia cell lines as well as effects of VEGF-specific antisense oligodeoxynucleotides (ASODN) on the growth of HL-60 cells. Meanwhile the methods to evaluate the VEGF level in the serum of patients with acute leukemia were explored. The levels of bFGF and VEGF in the serum from 32 patients with acute leukemia and 10 healthy subjects and in the supernatants of 5 various human leukemia cell lines were quantified by means of the enzyme-linked immunosorbent assay (ELISA) and were compared. VEGF levels were evaluated not only without standardization but also after standardized by platelet and finally expressed as VEGF/PLT (pg/10(6)). After with different concentrations of VEGF ASODN, HL-60 cell viability was examined with MTT assay and VEGF levels in supernatants were measured with ELISA, respectively. The results showed that bFGF was detected (3 pg/ml) in 14 out of 32 serum samples from patients with acute leukemia, and the positive (37.5%) was significantly higher than that in healthy controls (10%) (P < 0.01). 3 out of 5 supernanant samples obtained from leukemia cell lines demonstrated positive for bFGF as well. There is no difference of the serum VEGF levels between leukemia patients and healthy controls, but the serum VEGF levels in the serum from leukemia patients were significantly higher than those in healthy controls (P < 0.05) after standardization. 4 out of 5 leukemia cell (U937 excluded) were found to express VEGF in the supernanant. After exposure of HL-60 cells to VEGF ASODN at a concentration of 0.5, 1 and 5 micromol/L for 24 hours, the cell viability gradually dropped down to lower levels (P < 0.05 vs controls). After treatment of HL-60 cells with VEGF ASODN at a concentration of 1, 5 and 20 micromol/L for 24 hours, the VEGF levels in supernatants of target cells decreased (P < 0.05 vs controls). The patients with acute leukemia represented the higher levels of serum bFGF and VEGF than controls. Most of leukemia cell lines expressed bFGF and VEGF at different levels. It is concluded that bFGF and VEGF both have effects on regulations of angiogenesis in acute leukemia, but VEGF plays a pivotal role. VEGF-specific ASODN may have a role in them VEGF expression downregulated. Different results may be obtained in the evaluation of VEGF levels in the serum of patients with acute leukemia if different calculation methods are used. The methods reported can measure leukemia associated VEGF more accurately.
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PMID:[Expression of bFGF and VEGF in acute leukemia and its effects on HL-60 cell growth]. 1574 43

The mammalian target of rapamycin (mTOR) has recently been described to be constitutively activated in Bcr-Abl-transformed cells and to mediate rapamycin-induced inhibition of growth in respective cell lines. We have recently shown that rapamycin down-regulates expression of vascular endothelial growth factor (VEGF), a mediator of leukemia-associated angiogenesis, in primary CML cells. In the present study, we analyzed growth-inhibitory in vitro and in vivo effects of rapamycin on primary CML cells and asked whether rapamycin-induced suppression of VEGF in leukemic cells is related to growth inhibition. Rapamycin dose dependently inhibited growth of primary CML cells obtained from patients with imatinib-responsive or imatinib-resistant disease as well as growth of Bcr-Abl-transformed imatinib-resistant cell lines. Moreover, we observed potent cytoreductive effects of rapamycin in a patient with imatinib-resistant Bcr-Abl+ leukemia. The growth-inhibitory effects of rapamycin on CML cells were found to be associated with G1 cell cycle arrest and with induction of apoptosis. In all cell types tested, rapamycin was found to down-regulate expression of VEGF. However, exogenously added VEGF did not counteract the rapamycin-induced decrease in proliferation. In conclusion, rapamycin inhibits growth of CML cells in vitro and in vivo and, in addition, down-regulates expression of VEGF. Both effects may contribute to the antileukemic activity of the drug in CML.
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PMID:Identification of mTOR as a novel bifunctional target in chronic myeloid leukemia: dissection of growth-inhibitory and VEGF-suppressive effects of rapamycin in leukemic cells. 1578 22

Meisoindigo, an active compound of a Chinese anti-leukemia medicine, has been effectively used in the treatment of chronic myelogenous leukemia (CML). Increasing evidences have demonstrated that angiogenesis is an important pathobiologic feature of CML. The anti-angiogenesis effect of meisoindigo on CML is unknown. In this study, we determined the effects of meisoindigo on the apoptosis, adherence and differentiation of endothelial cells as well as the secretion of vascular endothelial growth factor (VEGF) by CML cells. We found that VEGF level, measured by enzyme-linked immunosorbent assay (ELISA), was higher in bone marrow plasma from CML patients compared with the healthy controls (334.83+/-23.09 ng/L versus 102.36+/-38.76 ng/L, P<0.01). CML cell VEGF production was decreased after CML cells were treated with 10 micromol/L meisoindigo compared with the controls (212.10+/-46.13 ng/L versus 293.75+/-64.79 ng/L, P<0.05). Ten micromole per liter of meisoindigo could induce time-dependent apoptosis of ECV304 cells determined by annexin-V. Treatment of ECV304 cells with meisoindigo for 48 h reduced the number of adherent cells and the expression of VCAM-1 compared with the control cells (43.78+/-9.09% versus 73.51+/-3.21%, P<0.05). Meisoindigo also inhibited tubule formation of HUVECs in an in vitro Matrigel after HUVECs were incubated with meisoindigo for 6 h. Our findings suggest that meisoindigo could inhibit angiogeneic process through decreasing the VEGF secretion in leukemic cells and also through inhibiting the proliferation, adhesion and differentiation of endothelial cells, causing the interruption of a reciprocal stimulatory loop between leukemic and endothelial cells. This effect may contribute to the anti-leukemic effect of this drug.
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PMID:Anti-angiogenesis effects of meisoindigo on chronic myelogenous leukemia in vitro. 1598 34

The present study evaluated the serum levels of known angiogenic factors and analysed their prognostic significance in patients with acute or chronic leukemia. Enzyme-linked immunosorbent assays (ELISAs) were performed to quantify the basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), tumor necrosis factor-alpha (TNF-alpha), angiogenin, and matrix metalloproteinase-9 (MMP-9) in stored samples obtained before treatment from patients with acute myeloid leukemia (AML; 30 patients), acute lymphoblastic leukemia (ALL; 10 patients), and chronic myelogenous leukemia (CML; 14 patients). The levels of VEGF, HGF, angiogenin, and MMP-9 were all significantly higher in patients with CML than in healthy individuals. The HGF levels were also higher in patients with AML than in healthy individuals, plus there was a significant correlation between the HGF level and the white blood cell count, monocyte count, and serum level of lactate dehydrogenase (LDH) in patients with AML. In a univariate analysis, age and HGF level were both found to be significant parameters predictive for an achievement of complete remission (CR) in patients with AML. Meanwhile, in a multivariate analysis using a logistic regression model, the HGF level was the only parameter strongly predictive for CR (P=0.047). The leukemia-free survival (LFS) rate for AML patients with a lower HGF concentration was better than that for AML patients with a higher HGF concentration (1 year LFS rates=75.0% vs. 37.5%, P=0.065). The HGF concentration was an independent prognostic factor for an achievement of CR, plus higher HGF concentrations were associated with a lower survival in patients with AML.
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PMID:Clinical implications of angiogenic factors in patients with acute or chronic leukemia: hepatocyte growth factor levels have prognostic impact, especially in patients with acute myeloid leukemia. 1601 34

We aimed to study the expression of phosphorylated vascular endothelial growth factor receptor 2 (pVEGFR-2), a membrane-bound tyrosine kinase receptor to vascular endothelial growth factor, in 76 cases of leukemia and nonneoplastic myeloproliferative disease and in 8 reactive bone marrows. The microvessel density (MVD) and the expression of both pVEGFR-2 and its ligand, VEGFA, were evaluated in these cases. We used archival cases and immunohistochemistry with a monoclonal antibody generated by us to the autophosphorylation sites in the cytoplasmic tail of VEGFR-2 and von Willebrand factor antibody to evaluate MVD. Our results demonstrate increased expression of this phosphorylated receptor in the neoplastic cells in acute myeloid and lymphoblastic leukemias. This correlated with increased MVD and VEGFA expression by the neoplastic cells. Interestingly, there was nuclear relocation of this receptor in these diseases. This raises the possibility that pVEGFR-2 may be involved in the transcriptional regulation of these leukemias. Small molecule inhibitors to this receptor may therefore be a useful adjunct in the therapy for these diseases.
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PMID:Expression and cellular localization of vascular endothelial growth factor A and its receptors in acute and chronic leukemias: an immunohistochemical study. 1608 50


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