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)

Proteinase-3 (PR-3) is a neutral serine proteinase present in the azurophil granules of human polymorphonuclear leukocytes. It degrades a variety of extracellular matrix proteins including elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters. It is identical to the target autoantigen (c-ANCA) associated with Wegener's granulomatosis and to myeloblastin, a serine proteinase first identified in HL-60 leukemia cells. In this study, the gene encoding PR-3 was cloned and sequenced. The gene spans approximately 6.5 kilobase pairs and consists of five exons and four introns. The genomic organization of PR-3 is similar to that of the other serine proteinases expressed in hemopoietic cells. Each residue of the catalytic triad of PR-3 is located on a separate exon, and the positions of the residues within the exons are similar to those in human leukocyte elastase and cathepsin G. The phase and placement of the introns in the PR-3 gene are also similar to those in human leukocyte elastase and cathepsin G. The 400-base pair (bp) 5'-flanking sequence of the PR-3 gene contains a TATA box at position 379. There is no CAAT box promoter element. The 3'-untranslated region is 200 bp, extending from a TGA stop codon to the site of polyadenylation 10 bp after the canonical AATAAA signal. Amplification of PR-3 from a human/hamster hybrid cell line localizes the gene to human chromosome 19. Evidence from Northern analysis suggests that PR-3 expression is primarily confined to the promyelocytic/myelocytic stage of bone marrow development.
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PMID:Structure, chromosomal assignment, and expression of the gene for proteinase-3. The Wegener's granulomatosis autoantigen. 140 Apr 30

Myeloblastin is a serine protease that has been identified in the human leukemia cell line HL-60. Down-regulation of this protease can inhibit proliferation and induce differentiation of promyelocyte-like human leukemic cells. Proteinase 3, a serine protease of human neutrophils, has been identified as the Wegener autoantigen. A high level of homology between myeloblastin and proteinase 3 has suggested that they may be a single serine protease. We have recently completed the 5'-terminal nucleotide sequence of proteinase 3 and shown that its mRNA was also expressed in HL-60 cells and in cells from patients with acute myeloid leukemia. Here we demonstrate that myeloblastin and proteinase 3 are encoded by a single mRNA.
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PMID:Wegener autoantigen and myeloblastin are encoded by a single mRNA. 168 49

Cells from the human leukemia cell line HL-60 undergo terminal differentiation when exposed to inducing agents. Differentiation of these cells is always accompanied by withdrawal from the cell cycle. Here we describe the isolation of a cDNA encoding a novel serine protease that is present in HL-60 cells and is down-regulated during induced differentiation of these cells. We have named this protease myeloblastin. Down-regulation of myeloblastin mRNA occurs with both monocytic and granulocytic inducers. Myeloblastin mRNA is undetectable in fully differentiated HL-60 cells as well as in human peripheral blood monocytes. We found that regulation of myeloblastin mRNA in HL-60 cells is serum dependent. Inhibition of myeloblastin expression by an antisense oligodeoxynucleotide inhibits proliferation and induces differentiation of promyelocyte-like leukemia cells.
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PMID:Down-regulation of a serine protease, myeloblastin, causes growth arrest and differentiation of promyelocytic leukemia cells. 259 67

Three human monocytic cell lines, U-937, THP-1 and Mono Mac 6 have, because of their morphology and staining properties, been classed as cell lines frozen in a window of the monocyte differentiation lineage corresponding to monoblasts and/or immature monocytes. These cell lines were analyzed for expression of a panel of hematopoietic differentiation markers by Northern blot analysis. They were all found to express one or several biochemical markers characteristic of immature cells in monocytic development, including myeloperoxidase, N-elastase, cathepsin G, myeloblastin, and azurocidin. Normal peripheral blood monocytes did not express these markers. Moreover, several markers expressed at high levels in mature monocytes, such as lysozyme, CD14, MHC class II and alpha-1 antitrypsin were either not expressed or were expressed only at low levels in the three cell lines analyzed. These results show that arrested differentiation at a relatively early stage of monoblast development is a common denominator for these human monocytic cell lines. Thus, transforming mutations acting at such an immature differentiation stage may frequently lead to neoplastic transformation, whereas similar mutations occurring at a more mature differentiation stage never give rise to any leukemias due to the loss of proliferative potential in committed cells.
Leukemia 1994 Sep
PMID:Human cell lines U-937, THP-1 and Mono Mac 6 represent relatively immature cells of the monocyte-macrophage cell lineage. 809 34

Retinoic acid is known to induce differentiation of human myeloid leukemia cells in vitro. Recently, all-trans retinoic acid has been used to induce remissions in patients with acute promyelocytic leukemia, probably through differentiation of the leukemia cells. Myeloblastin (mbn) is a protease that has been identified in the human leukemia cell line HL-60. Downregulation of this protease can inhibit proliferation and induce differentiation of HL-60-derived leukemia cells. Here we have investigated the regulation of mbn messenger RNA (mRNA) expression in two human leukemia cell lines, HL-60 and NB4, treated with all-trans retinoic acid. Under this treatment, downregulation of mbn mRNA was observed in both cell lines, but was considerably delayed in NB4 cells that carry the t(15;17) translocation characteristic of acute promyelocytic leukemia. We have found that multiple mechanisms were involved in the control of mbn mRNA expression. These mechanisms were different in HL-60 and NB4 cells. Our results show that in HL-60 cells, all-trans retinoic acid rapidly decreased transcription of mbn. In contrast, in the t(15;17)-positive NB4 cells treated with all-trans retinoic acid, upregulation of mbn mRNA expression was followed by a late downregulation, both achieved via posttranscriptional mechanisms.
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PMID:Regulation of myeloblastin messenger RNA expression in myeloid leukemia cells treated with all-trans retinoic acid. 842 65

Myeloblastin (mbn) is a serine protease involved in the control of growth and differentiation of human leukemic cells. In the promyelocytic-like human leukemia cell line HL-60 this protease is inhibited during retinoic acid (RA) induced differentiation. The t(15;17) translocation, specifically associated with the human acute promyelocytic leukemia (APL), fuses the retinoic acid receptor alpha (RAR alpha) to a novel gene PML generating the hybrid protein PML-RAR. We have shown that while mbn was early down-regulated in HL60 cells treated with all trans RA, the inhibition of this gene was considerably delayed in NB4 cells, which carry the t(15;17) translocation, upon treatment with the same inducer. This observation suggested that the changes in the myeloblastin regulation by RA found in NB4 cells could be ascribed to the presence of the fusion protein PML-RAR. To verify this hypothesis we have cloned the putative promoter region of mbn gene. Transactivation properties of endogenous retinoic acid receptors on this region have been tested in transfection experiments of HL60 and NB4 cell lines before and after treatment with all trans RA. We found that RA induced a significant inhibition of the luciferase reporter gene in HL60 cells. In contrast, a strong stimulation of luciferase activity was observed in NB4 cells treated with RA. The analysis of the promoter region allowed us to identify a new response element for retinoic acid receptors, named mREpal, which is probably affected by the product of t(15;17) translocation.
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PMID:[Effect of translocation t(15;17) on the gene expression regulation of myeloblastin during all trans retinoic acid induced myeloid differentiation in human leukemic cells]. 856 66

We previously showed (E. Clave et al., J. Immunother., 22: 1-6, 1999; J. Molldrem et al., Blood, 88: 2450-2457, 1996) that PR1, a human-lymphocyte-antigen (HLA)-A2.1-restricted peptide from proteinase 3, could be used to elicit CTLs from normal individuals. These CTLs showed HLA-restricted cytotoxicity and colony inhibition of myeloid leukemia cells that overexpress proteinase 3. In this study, we constructed a phycoerythrin-labeled PR1-HLA-A2 tetramer to identify PR1-specific CTLs by flow cytometry. No peripheral blood lymphocytes from three HLA-2.1+ donors stained with the tetramer, but, after 20 days in culture with weekly PR1 stimulation, 2-8% became tetramer+. Tetramer staining identified up to 40-fold more PR1-specific CTLs than were identified by limiting dilution analysis and correlated better with lysis of PR1-coated T2 cells (R2 = 0.95 versus R2 = 0.76). Tetramer+ CTLs were memory phenotype (91% CD45RO+), and most (58% CD95+) were activated. Tetramer-sorted allogeneic CTLs produced 83% lysis of HLA-A2.1+ chronic myelogenous leukemia (CML) blasts at an E:T ratio of 2.5:1, compared with 23% lysis by nonsorted CTLs, with no background lysis of HLA-A2.1+ normal cells. Cytoplasmic proteinase-3 expression was one log greater in CML blasts than in normal granulocytes. These results show that a PR1-HLA-A2 tetramer can be used to identify and select CTLs from normal donors that preferentially lyse CML cells, which could be used for leukemia-specific adoptive immunotherapy.
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PMID:A PR1-human leukocyte antigen-A2 tetramer can be used to isolate low-frequency cytotoxic T lymphocytes from healthy donors that selectively lyse chronic myelogenous leukemia. 1036 91

Proteinase-3/Myeloblastin (Mbn) is a neutral serine protease and a major constituent of the primary granules of myeloid cells. It can degrade extracellular matrix proteins and has been discussed as a key factor for the initiation of terminal differentiation in promyelocytic cells. Regulation of Mbn closely parallels that of another major primary granule protein, myeloperoxidase (MPO). We examined the expression and DNA methylation of Mbn in a model of in vitro differentiation of CD34+ enriched peripheral blood progenitor cells (PBPCs), and in various other myeloid and non-myeloid tissues. Mbn mRNA was undetectable in uncultured PBPCs but was upregulated during their in vitro differentiation. Its expression was enhanced in the presence of G-CSF. Mbn expression was also detected in several myeloid cell lines but not in mature granulocytes, monocytes and macrophages. Partial demethylation at a CpG site within Mbn intron 1 (analyzed by restriction with SmaI) was observed during continued in vitro differentiation of PBPCs. This site was fully demethylated in mature granulocytes, monocytes and macrophages. Variable methylation of this site and a second SmaI site located upstream of the putative Mbn promoter region was present in other myeloid and non-myeloid tissues examined.
Leukemia 1999 Sep
PMID:Cytosine demethylation of the proteinase-3/myeloblastin primary granule protease gene during phagocyte development. 1048 94

Bile acids were shown previously to inhibit proliferation and to induce monocytic differentiation in HL60 human acute promyelocytic leukemia cells (A. Zimber et al., Int. J. Cancer, 59: 71-77, 1994). In this report, we hypothesized that bile acids may exert a positive cooperativity with two known inducers of leukemic cell differentiation, all-trans retinoic acid and 1,25(OH)2-vitamin D3. Our results provide evidence that bile acids induced the monocytic differentiation of HL60 and THP-1 human leukemia cells exposed to ineffective concentrations of these inducers. The protein kinase C (PKC) inhibitors H-7 (10 and 20 microM) and staurosporine (5 and 20 nM) modulated the effects of bile acids on HL60 cell differentiation. Most interestingly, bile acids are shown herein to down-regulate the expression of the serine protease myeloblastin gene involved in the differentiation of myeloid hematopoietic cells. In agreement with the recent identification of nuclear receptors for bile acids, our data suggest that functional interactions between nuclear bile acid signaling pathways, PKC, and nuclear receptors for retinoic acid and vitamin D3 are involved in the down-regulation of the myeloblastin gene and the induction of cell differentiation in human leukemic cells.
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PMID:Functional interactions between bile acids, all-trans retinoic acid, and 1,25-dihydroxy-vitamin D3 on monocytic differentiation and myeloblastin gene down-regulation in HL60 and THP-1 human leukemia cells. 1067 52

Hematopoiesis depends on a pool of quiescent hematopoietic stem/progenitor cells. When exposed to specific cytokines, a portion of these cells enters the cell cycle to generate an amplified progeny. Myeloblastin (MBN) initially was described as involved in proliferation of human leukemia cells. The granulocyte colony-stimulating factor (G-CSF), which stimulates the proliferation of granulocytic precursors, up-regulates MBN expression. Here we show that constitutive overexpression of MBN confers factor-independent growth to murine bone marrow-derived Ba/F3/G-CSFR cells. Our results point to MBN as a G-CSF responsive gene critical to factor-independent growth and indicate that expression of the G-CSF receptor is a prerequisite to this process. A 91-bp MBN promoter region containing PU.1, C/EBP, and c-Myb binding sites is responsive to G-CSF treatment. Although PU.1, C/EBP, and c-Myb transcription factors all were critical for expression of MBN, its up-regulation by G-CSF was associated mainly with PU.1. These findings suggest that MBN is an important target of PU.1 and a key protease for factor-independent growth of hematopoietic cells.
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PMID:Myeloblastin is a granulocyte colony-stimulating factor-responsive gene conferring factor-independent growth to hematopoietic cells. 1067 5


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