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)

When added to RPMI-1640 medium containing fetal bovine serum, DNA-directed antineoplastic agents such as cytosine arabinoside (araC), daunorubicin, and actinomycin D induce the monocytic differentiation of ML-1 human myeloblastic leukemia cell populations to an extent that depends upon both drug and serum concentration. Differentiation is not induced in the absence of serum or when antibodies to tumor necrosis factor-alpha and transforming growth factor-beta are added to the cultures, indicating that these serum-contained cytokines participate in initiating the differentiation process. The drug- and cytokine-dependent cell maturation, which results in the inhibition of leukemic cell growth, is achieved at much lower concentrations of drug than is required for growth-inhibition through drug-mediated cell kill. RNA- and protein-targeted agents cannot replace DNA-specific agents in the process of differentiation-induction. The DNA-specific agents render the leukemic cells responsive to the low concentrations of differentiation-inducing cytokines that are present in serum, causing them to mature, and subsequently, to cease growth. This sensitization may be a component of the clinically selective action of DNA-specific antitumor agents.
Leukemia 1993 Aug
PMID:Dynamics of interaction between DNA-specific antitumor agents and serum-contained cytokines in the initiation of ML-1 human myeloblastic leukemia cell differentiation. 835 Jun 21

Endoglin is a homodimeric membrane glycoprotein primarily associated with human vascular endothelium. It is also found on bone marrow proerythroblasts, activated monocytes and on lymphoblasts in childhood leukemia. Endoglin has recently been described as a component of the transforming growth factor-beta (TGF-beta) receptor system as it can bind TGF-beta 1 with high affinity. We now report on the localization of the human endoglin gene (END) to human chromosome 9, by Southern blot analysis of BglII fragments of DNA from human-hamster somatic cell hybrids. This chromosomal localization was confirmed by fluorescent in situ hybridization coupled with Distamicin A (DA)/4',6-diamidino-2-phenylindole (DAPI) banding on human chromosomes. The regional localization was assigned to 9q34-->qter by GTG-banding (G-banding by trypsin using Giemsa stain), indicating a telomeric position with respect to the Philadelphia breakpoint.
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PMID:Assignment of the human endoglin gene (END) to 9q34-->qter. 840 38

The current hypothesis for the pathogenesis of myelofibrosis involves the intramedullary release of growth factors from defective or abnormal megakaryocytes. We describe a case of an acute micromegakaryocytic leukaemia, in a patient with chronic myelofibrosis, that provides additional evidence for this concept. The micromegakaryocytes, which reached 223 x 10(9)/l, were characterized morphologically by both light and electron microscopy, immunocytochemically and by platelet peroxidase activity. The cells were shown to have a mature cytoplasm, containing alpha granules and the associated proteins; vWF:Ag, fibrinogen, fibronectin and protein S. DNA analysis, by both a Seescan Solitaire Plus image analysis system and flow cytometry, revealed nuclear immaturity, with 92% of cells being diploid. Serum markers of connective tissue synthesis, namely carboxy terminal peptide of procollagen I (PICP), procollagen terminal peptide III (PIIIP) and laminin all increased significantly following transformation and were associated with an increase in platelet-derived growth factor (PDGF) and transforming growth factor-beta (TGF-beta). These observations support the current hypothesis for bone marrow fibrosis formation and provide, for the first time, a link between in vivo growth factor release, bone marrow stromal turnover and megakaryocyte mass. In addition, the release of biologically active TGF-beta may explain both the increased fibronectin and angiogenesis characteristic of myelofibrotic bone marrow.
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PMID:Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis. 843 38

Uterine epithelial cells (UEC) isolated from 6-week-old CF-1 mice were immortalized using retroviral-mediated transfection of SV40 large T-antigen. One line, WEG-1, retained epithelial morphology and reacted with antibodies to cytokeratins 18, 19, laminin, fibronectin, and beta-catenin. In addition, WEG-1 cells displayed strong nuclear immunoreactivity to SV40 large T-antigen, confirming integration of the retrovirus vector and expression of this gene. WEG-1 cells were negative for nonepithelial markers such as desmin and factor 8. WEG-1 cells did not proliferate in serum-free medium; however, addition of 0.5% FBS supported proliferation to the same extent as 10% FBS. Addition of 50 ng/ml epidermal growth factor to medium containing 0.5% charcoal-stripped FBS restored proliferation comparable with 0.5% whole FBS. Epidermal growth factor or transforming growth factor-alpha (50 ng/ml), but not transforming growth factor-beta, leukemia-inhibiting factor, or fibroblast growth factor, induced the secretion of three proteins (M(r) approximately to 158K, 148K, and 36K). Comparison of protein secretions of WEG-1 cells and UEC showed shared as well as distinct bands. Like UEC, WEG-1 cells secreted PGF2a and PGE2 and expressed PG GH synthase-2. Unlike UEC, WEG-1 cells showed no apical/basal preference for either uptake of methionine or secretion of proteins. The absence of immunoreactive E-cadherin or zona occludens-1 was consistent with the absence of cell polarity in WEG-1 cells. Primary UEC, which polarize in vitro, do not support blastocyst attachment. WEG-1 cells, although not polarized in vitro, also exhibited delayed blastocyst attachment compared with nonuterine cell lines, suggesting that WEG-1 cells partially retained some aspects of UEC function relevant to embryo attachment. WEG-1 cells expressed messenger RNA for Muc-1, an UEC mucin suggested to have antiadhesive properties. Furthermore, WEG-1 cells did not display high affinity heparin binding sites, an activity associated with embryo attachment. WEG-1 cells may provide a model for studying various aspects of UEC function and murine embryo attachment.
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PMID:Production and characterization of WEG-1, an epidermal growth factor/transforming growth factor-alpha-responsive mouse uterine epithelial cell line. 853 10

Prostate tumor cells preferentially metastasize to bony sites and lymph nodes at a frequency in excess of that which would be predicted by random tumor cell dissemination. In order to determine whether chemoattractants in these organs promote organ-specific metastasis, we utilized human cell lines derived from and/or related to these organs as sources of potential chemoattractants. Secretory proteins derived from the cell lines MG-63 (osteosarcoma), SK-ES-1 (Ewing's sarcoma), and KG-1 (leukemia) stimulated chemomigration of the TSU-pr1 prostate tumor cells in a dose-dependent manner in Boyden chambers. In addition, secretory proteins from a human prostatic stromal cell line (hPS) and from the TSU-Pr1 prostate tumor cell line were also able to stimulate chemomigration of the TSU-pr1 cells through Boyden chambers. Since lymph nodes and bony sites represent organs of hematopoietic/lymphoid proliferation and activation, we undertook identification of specific cytokines present at these sites which may promote the chemomigration of prostate tumor cells. In this context, the cytokines interleukin-1 alpha, interleukin-2, interleukin-6, tumor necrosis factor-beta, transforming growth factor-beta, interferon alpha 2-a, and granulocyte-macrophage colony-stimulating factor did not stimulate chemomigration of the TSU-pr1 prostate tumor cell line. In contrast, the cytokine epidermal growth factor (EGF) stimulated chemomigration of the TSU-pr1 prostate tumor cells through the Boyden chambers in a dose-dependent manner. Western blot analysis of secretory proteins from the cell lines KG-1, SK-ES-1, MG-63, hPS, and TSU-pr1 identified EGF-immunoreactive proteins in all cases. In addition, EGF immunoreactivity was localized to the stroma of the human prostate, the osteogenic stroma of pelvic medullary bone, and the stroma within the capsule and trabeculae of pelvic lymph nodes. Hence, these results demonstrate that the cytokine EGF promotes the chemomigration of the TSU-pr1 prostate tumor cell line, and that EGF within the stroma of pelvic lymph nodes and medullary bone may act as a chemoattractant for prostate tumor cells, thereby facilitating the preferential formation of metastatic foci within these organs.
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PMID:Epidermal growth factor (EGF) promotes chemomigration of a human prostate tumor cell line, and EGF immunoreactive proteins are present at sites of metastasis in the stroma of lymph nodes and medullary bone. 854 75

The induction of tumor cell differentiation represents an attractive strategy for the treatment of a wide range of malignancies. Differentiation of HL-60 promyelocytic leukemia cells towards neutrophils or monocytes has been shown to induce apoptotic cell death, which is inhibited by bcl-2 over-expression. However, the role of the bcl-2 gene family during erythroid differentiation of human leukemia cells remains unknown. We found that human erythroleukemia (HEL) and K562, two leukemia cell lines that undergo erythroid differentiation do not express Bcl-2, but express Bcl-XL, a related protein that functions as an inhibitor of apoptosis. Differentiation of HEL or K562 cells with inducers of erythroid differentiation (hemin, retinoic acid, or transforming growth factor-beta) was accompanied by progressive cell death and degradation of genomic DNA into oligonucleosomal fragments. The loss of cellular viability was associated with downregulation of bcl-xL mRNA and protein. In contrast, the levels of Bax, another Bcl-2 family member implicated in apoptosis remained unaltered. Constitutive expression of Bcl-XL by gene transfer inhibited apoptosis triggered by erythroid differentiation of HEL K562 cells. Yet, Bcl-XL did not alter the expression of epsilon-globin, which is induced during erythoid differentiation of HEL and K562 cells, arguing that apoptosis and differentiation can be uncoupled by Bcl-XL. These results indicate that Bcl-XL acts as an antiapoptosis protein in leukemia cells that undergo erythroid differentiation and that downregulation of bcl-x is a component of the apoptotic response that is coupled to differentiation in human leukemia cells.
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PMID:Apoptosis induced by erythroid differentiation of human leukemia cell lines is inhibited by Bcl-XL. 861 10

The recently identified cyclin-dependent kinase inhibitor p15INK4B is localized to a region on chromosome 9p21 frequently deleted in human tumors. Previous evidence has pointed to a related gene, p16INK4A, as the principal target of this deletion. We report that in gliomas and, to a striking degree, in leukemias, the p15 gene is commonly inactivated in association with promoter region hypermethylation involving multiple sites in a 5'-CpG island. In some gliomas and all of the primary leukemias, this event occurs without alteration of the adjacent gene, p16INK4A. In other tumors, including lung, head and neck, breast, prostate, and colon cancer, inactivation of p15INK4B occurs only rarely and only with concomitant inactivation of p16. Aberrant methylation of p15INK4B is associated with transcriptional loss of this gene. Treatment with the demethylating agent 5-aza-2'-deoxycytidine leads to re-expression of p15 mRNA. In selected leukemia cell lines, p15 inactivation correlates with known resistance to the growth-suppressive effects of transforming growth factor-beta. These results suggest that p15INK4B is inactivated selectively in leukemias and gliomas and seems to constitute an important tumor suppressor gene loss in these neoplasms.
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PMID:Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. 863 Oct 3

Leukemia cell lines that do not proliferate in the absence of serum grow well when cultured with stromal cells. To study this growth dependence on stroma, we selected the M1 myeloblast clone, since its stroma dependence is reminiscent of that exhibited by hematopoietic stem cells. Conditioned medium form a stromal cell line, prepared under serum-free conditions, contained an activity that induced the proliferation of M1 cells and was therefore designated M1 myeloid activity (MMA). Among the various cytokines tested for MMA-like activity, only transforming growth factor-beta (TGF-beta) and macrophage colony-stimulating factor (M-CSF) were found to affect M1 cell survival, and the two cytokines acted synergistically to induce M1 cell growth. Antibodies to both TGF-beta and M-CSF abolished most, but not all, of the MMA in the medium conditioned by stromal cells, indicating that additional factors contribute to MMA. A subclone of M1 cells, M1/M2, selected in medium conditioned by stroma, was found to respond to stromal stimulation but was unable to proliferate in fetal calf serum (FCS). Neutralization experiments indicated that M1/2 cell growth depended mainly on M-CSF and also partially on TGF-beta. By contrast, the same neutralizing antibodies did not affect the ability of serum to support M1 cell growth. The molecules that promoted leukemia cell growth in serum seemed therefore to differ from those provided by stroma. This model system may offer novel information on the interactions of normal and leukemic hematopoietic cells with their stromal microenvironment.
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PMID:Interactions between leukemia cells and bone marrow stromal cells: stroma-supported growth vs. serum dependence and the roles of TGF-beta and M-CSF. 863 29

Stem cell factor (SCF) is an essential hematopoietic cytokine that interacts with other cytokines to preserve the viability of hematopoietic stem and progenitor cells, to influence their entry into the cell cycle and to facilitate their proliferation and differentiation. SCF on its own cannot drive noncycling hematopoietic progenitor cells into the cell cycle but does prevent their apoptotic death. SCF when combined with other cytokines increases the cloning efficacy of hematopoietic progenitor cells from all lineages. SCF also stimulates the growth of CD34+ leukemic progenitor cells from most patients with acute myeloid leukemia (AML). The mRNA expression of the SCF receptor c-kit has been shown to be significantly increased in all fresh AML blast cells compared with normal controls (healthy volunteers), in particular CD34+ cells. Two inhibitory cytokines, transforming growth factor-beta and interleukin-4, decreased c-kit expression, whereas tumor necrosis factor-alpha increased c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression, but chemotherapeutic drugs showed no effect on c-kit expression in AML cells. Apoptosis has been shown to be directly related to a high complete remission rate in AML patients following induction therapy. Since SCF has been shown to stimulate the proliferation of mainly CD34+ AML cells, we have investigated whether the poor response of patients with CD34+ myeloid leukemia cells to chemotherapy could be due to SCF-induced resistance to apoptosis. The effect of SCF on the apoptosis induced by chemotherapeutic drugs commonly used in the treatment of AML - cytarabine, daunorubicin and carboplatin - was examined in human CD34+ myeloid leukemia cells in serum-free cultures. SCF significantly reduced the induced apoptosis by more than 50% in all CD34+ human leukemia cells treated by any of the three chemotherapeutic drugs. Antibodies blocking c-kit reversed the significant inhibitory effect of SCF on chemotherapy-induced apoptosis, confirming the role of SCF in the resistance to chemotherapy-induced apoptosis in CD34+ human leukemia. These results suggest that the poor response of patients with CD34+ leukemia cells could be at least partially due to less chemotherapy-induced apoptosis resulting from protection by SCF as an adjuvant mechanism for drug resistance in myeloid leukemia. We conclude that an antisense strategy to block c-kit expression in AML blast cells may prove valuable for decreasing the chemoresistance of AML patients. The abrogation of leukemic resistance to apoptotic death through anti-SCF/c-pit expression combined with chemotherapy offers potential for designing novel therapeutic approaches for refractory AML patients.
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PMID:Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. 867 52

The Mov-13 strain of mice was created by the insertion of the murine Moloney leukemia virus into the first intron of the alpha 1 (I) collagen gene. Consequently, Mov-13 embryos do not transcribe alpha 1 (I) collagen mRNA and lack type I collagen protein in the extracellular matrix (ECM). Homozygotes die within 12-14 days of embryonic development, in part from the rupture of large blood vessels, and also exhibit deficiencies in hematopoesis and assembly of the ECM (Lohler et al. [1984] Cell 38:597-607). Several matricellular proteins, proteoglycans, and growth factors bind to type I collagen, e.g., fibronectin, secreted protein acidic and rich in cysteine (SPARC), decorin, and transforming growth factor-beta. Here we investigate the expression and function of SPARC in the absence of type I collagen. We show that fibroblasts isolated from Mov-13 homozygous, heterozygous, and wild-type embryos transcribed and translated SPARC mRNA in vitro. However, accumulation of extracellular SPARC was severely affected in the tissues of Mov-13 homozygotes, whereas extracellular deposition of the secreted glycoproteins fibronectin and type III collagen was not altered. Since SPARC has been shown to be a regulator of cell shape, the functional consequences of the absence of extracellular SPARC were evaluated in collagen gel contraction assays. Fibroblasts isolated from homozygous Mov-13 mice did not contract native type I collagen gels as efficiently as fibroblasts from heterozygous littermates; however, addition of exogenous SPARC enhanced the contraction of collagen by homozygous Mov-13 fibroblasts. The stimulatory effect of SPARC was blocked by antibodies specific for the amino terminus of the protein. These results provide evidence that type I collagen is one of the major extracellular proteins that binds SPARC in vivo. Furthermore, the capacity of fibroblasts to contract ECM in vitro is enhanced by extracellular SPARC. We therefore propose that the remodeling of ECM by cells in vivo is regulated in part by a specific interaction between SPARC and type I collagen.
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PMID:Type I collagen-deficient Mov-13 mice do not retain SPARC in the extracellular matrix: implications for fibroblast function. 890 20


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