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)

Mouse embryonic stem (ES) cells can be propagated in vitro while retaining their properties of pluripotency and self-renewal under the continuous presence of leukemia inhibitor factor (LIF). An essential role has been attributed to subsequent activation of the Stat3 transcription factor in mediating LIF self-renewal response. To date, however, downstream target genes of Stat3 in ES cells are still unknown. To isolate these genes, we performed a microarray-based kinetic comparison of LIF-stimulated (undifferentiated) ES cells versus ES cells induced to differentiate by shutting down Stat3 activity through either LIF deprivation or, more specifically, expression of a Stat3 dominant-negative mutant. In each case, we chose the earliest time at which ES cells lose their self-renewal properties, as illustrated by a decrease in the number of embryoid bodies and blast cell colony formation as well as germ layer marker expression. Comparison of the two independent approaches revealed similarly regulated genes that are likely to be involved in the Stat3 effects on ES cell self-renewal. For instance, upregulation of growth factors such as the transforming growth factor-beta relative Lefty1 or transcriptional regulators such as Id1 and Id2 and down-regulation of the groucho-like protein Aes1 (grg5) were found. Promoter analysis of the aes1 gene revealed three functional Stat3 consensus sites, as shown by luciferase assays. Furthermore, chromatin immunoprecipitation experiment demonstrated that Stat3 is recruited to the promoter of aes1 in ES cells. These data demonstrated that the aes1 gene is a direct transcriptional target of Stat3 in ES cells.
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PMID:Microarray analysis of LIF/Stat3 transcriptional targets in embryonic stem cells. 1609 94

The fusion of Abl with either Bcr or Tel in human leukaemia leads to the constitutive activation of Abl tyrosine kinase, which in turn induces growth-factor-independent proliferation and cell survival. However, the mechanism by which Bcr-Abl induces cellular transformation has not yet been well characterized. Here, we show that Bcr-Abl-expressing cells are resistant to growth inhibition and apoptosis mediated by transforming growth factor-beta (TGF-beta). Interestingly, we observed that the suppressive effects of Bcr-Abl on TGF-beta responses were not mediated by an impairment of Smad signalling, which is believed to act as the principal mediator of TGF-beta responses. In contrast, we found that Bcr-Abl can target the protein kinase AKT and the transcription factor Fox O3 to interfere with growth inhibition and apoptosis in response to TGF-beta. Our results show a novel mechanism of cellular transformation by the oncogenic fusion protein Bcr-Abl through suppression of the cytostatic actions of TGF-beta.
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PMID:Bcr-Abl activates the AKT/Fox O3 signalling pathway to restrict transforming growth factor-beta-mediated cytostatic signals. 1611 47

To investigate if the tumor suppressor properties of p57KIP2 are dependent on its DNA methylation status, we studied the impact of several stress stimuli in leukemic cell lines with different p57KIP2 promoter DNA methylation levels. p57KIP2 reactivation was observed after stimulation with transforming growth factor-beta, other cytokines, high-density culture or serum withdrawal in p57KIP2 promoter unmethylated cells but not in methylated cells. In these cells, p57KIP2 reactivation required the use of a hypomethylating agent or a histone deacetylase inhibitor. Overexpression of p57KIP2 in p57KIP2 promoter methylated leukemic cell lines resulted in cell growth arrest and the induction of apoptosis. In contrast, overexpression of p57KIP2 in partially methylated cells only resulted in a moderate inhibition of cell growth and had no impact on apoptosis. Transduction of unmethylated cells expressing high levels of p57KIP2 with p57KIP2 short hairpin RNA resulted in increased cell proliferation. These results suggest that the tumor suppressive properties of p57KIP2 in leukemia may depend on the intrinsic promoter DNA methylation status of the gene.
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PMID:Differential tumor suppressor properties and transforming growth factor-beta responsiveness of p57KIP2 in leukemia cells with aberrant p57KIP2 promoter DNA methylation. 1693 78

To investigate the regulatory mechanisms of angiogenesis in the development of myelodysplastic syndromes (MDS) and its progression to overt leukaemia (OL), bone marrow samples from control, paired samples from MDS patients before and after transformation to OL (MDS --> OL) and de novo acute myeloid leukaemia (AML) were analysed. Immunohistochemical staining showed a significant increase of bone marrow microvascular density (MVD) in MDS and de novo AML compared with controls. Surprisingly, in MDS, MVD significantly decreased upon transformation to OL, which was also significantly lower than the MVD of de novo AML. This evidence was strengthened by the pattern of angiogenic mediator gene expression, confirming the importance of various angiogenic mediators including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), tumour necrosis factor alpha (TNFalpha), hepatocyte growth factor (HGF) and the angiopoietin family of mediators (Ang-1 and Ang-2) as well as the receptors for angiogenic mediators, such as VEGF receptor 2 (VEGFR2) and the tyrosine kinase receptor, TIE2. By contrast, the anti-angiogenic mediator, transforming growth factor-beta (TGFbeta) exhibited significantly higher expression in the bone marrow of MDS --> OL, indicating the importance of this cytokine as the suppressive factor of angiogenesis in MDS. These findings indicate that the bone marrow microenvironment in MDS --> OL and de novo AML differs remarkably, suggesting the different efficacy of anti-angiogenic therapy between de novo AML and leukaemia secondary to MDS.
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PMID:Regulation of angiogenesis in the bone marrow of myelodysplastic syndromes transforming to overt leukaemia. 1740 59

Extensive bone marrow necrosis and symptomatic hypercalcemia have been described independently as rare complications of chronic myeloid leukemia. Here we report a 66-year-old man who developed B cell blastic transformation 10 years after diagnosis of CML in the chronic phase. Extensive bone marrow necrosis and symptomatic hypercalcemia concurrently developed after transformation, with development of disseminated intravascular coagulation and multifocal osteolysis. Most necrotic cells were readily identifiable as blasts. Mediators related to hypercalcemia, including prostaglandin E2, transforming growth factor-alpha and transforming growth factor-beta, were significantly elevated in the serum. As far as we know, this is the first case report of chronic myeloid leukemia concurrently developing bone marrow necrosis and hypercalcemia; this association was not reported in other types of leukemia or bone marrow malignancies.
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PMID:Extensive bone marrow necrosis and symptomatic hypercalcemia in B cell blastic transformation of chronic myeloid leukemia: report of a case and review of the literature. 1764 50

Implantation, a critical step for establishing pregnancy, requires molecular and cellular events resulting in healthy uterine growth and differentiation, blastocyst adhesion, invasion and placental formation. Successful implantation requires a receptive endometrium, a normal and functional embryo at the blastocyst stage and a synchronized dialogue between maternal and embryonic tissues. In addition to the main role of sex steroids, the complexity of embryo implantation and placentation is exemplified by the number of cytokines and growth factors with demonstrated roles in these processes. Disturbances of the normal expression and action of these cytokines result in absolute or partial failure of implantation and abnormal placental formation in mice and humans. Members of the gp130 cytokine family, interleukin (IL)-11 and leukaemia inhibitory factor, the transforming growth factor-beta superfamily, colony-stimulating factors, and the IL-1 and IL-15 systems are all crucial for successful implantation. In addition, chemokines are important both in recruiting specific cohorts of leukocytes to the implantation site, and in trophoblast trafficking and differentiation. This review provides discussion on embryonic and uterine factors that are involved in the process of implantation in autocrine, paracrine and/or juxtacrine manners at hormonal, cellular, and molecular levels.
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PMID:Basic aspects of implantation. 1806 73

The aim of the present study was to assess genes expressed in maternal uterine tissue and pre-implantation embryos which are presumably involved in maternal recognition and establishment of canine pregnancy. For this purpose, 10 pregnant bitches were ovariohysterectomized between days 10 and 12 after mating. Four non-pregnant bitches served as controls. Early pregnancy was verified by flushing the uterine horns with PBS solution. The collected embryos (n = 60) were stored deep-frozen (-80 degrees C). Uterine tissue was excised, snaps frozen in liquid nitrogen and homogenized using TRI Reagent. All embryos from one litter were thawed together and also homogenized in TRI Reagent. RT-PCR was performed to prove mRNA expression of progesterone receptor, key enzymes of the prostaglandin synthesis pathway, selected growth factors, cytokines, immune cell receptors, major histocompatibility complex (MHC) and matrix-metalloproteinases (MMP). Only pregnant uteri revealed the presence of mRNA for interferon (IFN)-gamma, IL-4 and CD-8, which resembles the milieu in humans and other mammalians. Similarly, in day 10 embryos, mRNA for transforming growth factor-beta, insulin-like growth factor-1,-2, hepatocyte growth factor, leukaemia inhibitor factor, tumour necrosis factor-alpha, interleukin-1beta,-6,-8, cyclooxygenase-2, CD4(+) cells, and MMP-2 and -9 were detected, but not MHC-I or -II. We therefore suppose that the canine embryo, like its human counterpart, actively initiates measures to prevent attacks from the maternal immune system to prepare its own adhesion, nidation, growth and further development.
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PMID:Expression of genes in the canine pre-implantation uterus and embryo: implications for an active role of the embryo before and during invasion. 1839 90

Bone morphogenetic proteins (BMP), belonging to the transforming growth factor-beta superfamily, are multifunctional regulators of cell proliferation, differentiation and apoptosis in various types of malignant cells. In this study, we investigated BMP-6 promoter methylation in patients with various types of leukemias. The BMP-6 methylation was found preferentially in adult T-cell leukemia (ATL) (49 of 60, 82%) compared with other types of leukemias studied including acute myeloid leukemia (3 of 67, 5%), acute lymphoblastic leukemia (6 of 38, 16%) and chronic lymphocytic leukemia (1 of 21, 5%). Among subtypes of ATL, the BMP-6 gene was more frequently methylated in aggressive ATL forms of acute (96%) and lymphoma (94%) types than less malignant chronic ATL (44%) and smoldering ATL (20%). We also analyzed the methylation status of peripheral blood mononuclear cells from healthy donors and nonmalignant lymph nodes with reactive lymphadenopathy, none of which showed detectable BMP-6 methylation in this study. The BMP-6 methyaltion was correlated with decreased mRNA transcript and protein expression. Expression of BMP-6 was restored by the demethylating agent 5-aza-2'-deoxycytidine, suggesting that methylation was associated with the transcriptional silencing. Serial analysis demonstrated an increasing methylation of CpG sites in the BMP-6 promoter and the resultant suppression of BMP-6 expression as ATL progressed. These findings suggested that BMP-6 promoter methylation is likely to be a common epigenetic event at later stages of ATL and that the methylation profiles may be useful for the staging of ATL as well as for evaluation of the individual risk of developing the disease.
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PMID:Promoter methylation of the bone morphogenetic protein-6 gene in association with adult T-cell leukemia. 1868 53

The ecotropic viral integration site-1 (Evi-1) gene was first identified as a common locus of retroviral integration in murine leukemia models. In humans, EVI-1 is located on chromosome 3q26, and rearrangements on chromosome 3q26 often activate EVI-1 expression in hematological malignancies. Overexpression of EVI-1 also occurs with high frequency in leukemia patients without 3q26 abnormalities, and importantly, high EVI-1 expression is an independent negative prognostic indicator irrespective of the presence of 3q26 rearrangements. Recent gene targeting studies in mice revealed that Evi-1 is preferentially expressed in hematopoietic stem cells and plays an essential role in proliferation and maintenance of hematopoietic stem cells. In addition, intense attention has been focused on the EVI-1 gene complex as retrovirus integration sites because transcription-activating integrations into the EVI-1 locus confer survival and self-renewing ability to hematopoietic cells. The experimental results using animal models suggest that activation of Evi-1 in hematopoietic cells leads to clonal expansion or dysplastic hematopoiesis, whereas onset of full-blown leukemia requires cooperative genetic events. EVI-1 possesses diverse functions as an oncoprotein, including suppression of transforming growth factor-beta-mediated growth inhibition, upregulation of GATA2, inhibition of the Jun kinase pathway, and stimulation of cell growth via activator protein-1. In this article, we summarize current knowledge regarding the biochemical properties and biological functions of EVI-1 in normal and malignant hematopoiesis, with specific focus on its pathogenetic significance in hematological malignancies.
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PMID:Pathogenetic significance of ecotropic viral integration site-1 in hematological malignancies. 1938 66

Notch-signalling has been implicated as a pathogenetic factor and a therapeutical target in T-cell leukaemias and in some lymphomas of B-cell origin. Our aim was to investigate the role of Notch-signalling in apoptosis regulation in human non-Hodgkin B-cell lymphoma (B-NHL) cell lines and in primary chronic lymhocytic leukaemia (CLL) cells using Delta-like 4 (Dll4) ligand mediated Notch activation and gamma-secretase inhibitor (GSI) mediated Notch inhibition in vitro. The potential cross-talk of Notch with the transforming growth factor-beta (TGFb) pathway in apoptosis induction was also explored, and the effect of GSI on drug-induced apoptosis was assessed. Modulation of Notch-signalling by itself did not change the rate of apoptosis in B-NHL cell lines and in CLL cells. TGFb-induced apoptosis was decreased - but not completely abolished - by GSI in TGFb-sensitive cell lines, but resistance to the apoptotic effects of TGFb were not reversed by Notch activation or inhibition. Drug-induced apoptosis was not modified by GSI. We identified Hairy/Enhancer of Split (HES)-1 as a TGFb target gene in selected - TGFb-sensitive - B-NHL cell lines. TGFb-induced HES-1 was only partially Notch-dependent in later phases. Apoptosis regulation by TGFb and GSI was not dependent on the transcriptional regulation of c-myc. In conclusion, our data does not support a unifying role of Notch in regulating apoptosis in B-NHL, but warns that gamma-secretase inhibitors may actually counteract apoptosis in some cases.
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PMID:Notch-regulation upon Dll4-stimulation of TGFb-induced apoptosis and gene expression in human B-cell non-Hodgkin lymphomas. 2001 7


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