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)

The human leukemia cell line KU812 had been described as an immature prebasophilic cell line and exhibits a potential to differentiate into mature basophils. We studied the effect of interleukin-4 (IL-4) on the basophilic differentiation of KU812 cells. When KU812 cells were cultured with 1 ng/ml IL-4, cellular histamine content increased more than 10-fold. IL-4 also enhanced the expression of Fc epsilon RI alpha, a high affinity IgE receptor, on the cell surface. KU812 cells treated with IL-4 expressed higher levels of Fc epsilon RI alpha, Fc epsilon RI beta and Fc epsilon RI gamma mRNA than non treated KU812 cells. After 21 days in culture with IL-4, KU812 cells became morphologically mature basophilic cells as demonstrated by staining positive for cytoplasmic granules and heparin proteoglycan by Wright dye and toluidin blue dye respectively. In addition, IgE-mediated histamine release was observed, suggesting that the Fc epsilon RI induced by IL-4 was functional and was able to transduce a signal for degranulation. These results suggest that IL-4 promotes differentiation of KU812 cells into mature basophilic cells both morphologically and functionally.
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PMID:Basophilic differentiation of the human leukemia cell line KU812 upon treatment with interleukin-4. 964 30

We show that in the rat basophilic leukemia cell line RBL, the physiological stimulation of the IgE receptor or direct activation of PKC leads to the missorting of proteins to the plasma membrane, diverting them from their normal intracellular destination. This is demonstrated for two classes of proteins that are normally targeted to the secretory lysosomes via completely different mechanisms, i.e. proteoglycans and the aspartic protease cathepsin D. In the latter case, normal processing of the enzyme is also affected, leading to secretion of the immature form of cathepsin. The present study shows how completely different sorting mechanisms, such as those for delivering proteoglycans and cathepsin D to secretory lysosomes, might share common regulatory signals and are similarly affected when the levels of these signals are perturbed. Finally, protein kinase C appears to be a major player in the signal transduction pathways, leading to proteoglycan and cathepsin D missorting.
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PMID:Regulation of protein sorting at the TGN by plasma membrane receptor activation. 1065 66

Oncostatin M (OSM) and leukaemia inhibitory factor (LIF) exhibit pleiotropic biological activities and share many structural and genetic features. The two cytokines bind with high affinity to the same receptor (LIF/OSM receptor), which consists of the LIF receptor alpha chain (LIFRalpha) and the signal transduction unit gp130. A soluble form of the beta chain of the receptor complex called soluble gp130 (sgp130) has been cloned. In this study, we sought to determine whether recombinant sgp130 or anti-gp130 Ab could attenuate the resorption of proteoglycans induced by OSM and LIF in articular cartilage explants. The results show that at high concentrations sgp130 is capable of attenuating both LIF and OSM mediated resorption. In contrast, anti-gp130 Ab selectively inhibited the stimulation of proteoglycan (PG) release by OSM, albeit minimally. The failure of anti-gp130 to attenuate LIF stimulated PG resorption may be due to the normal interaction of LIF with LIFRalpha and unfettered heterodimerization of LIFRalpha with gp130 in the presence of the antibody. The results indicate that sgp130 and anti-gp130 can modulate cartilage PG metabolism in vitro. Whether sgp130 may have therapeutic activity in models of arthritis or indeed in arthritic diseases remains to be determined.
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PMID:Soluble glycoprotein 130 (gp130) attenuates OSM- and LIF-induced cartilage proteoglycan catabolism. 1067

Translocations involving 11q23 are among the most common genetic abnormalities in hematologic malignancies, occurring in approximately 5-10% of acute lymphoblastic leukemia (ALL) and 5% of acute myeloblastic leukemia (AML). In 11q23 translocations, the mixed lineage leukemia (MLL) gene on chromosome 11, band q23, is usually disrupted. The human homologue of the rat NG2 chondroitin sulfate proteoglycan molecule, as detected by the monoclonal antibody (moab) 7.1, was shown to be expressed on leukemic cells with MLL rearrangements of children with acute leukemia. We further investigated the reactivity of the moab 7.1 on 533 cell samples of adults (n = 215) and children (n = 318) with acute leukemias (271 AML, 217 B-lineage ALL, 37 T-lineage ALL, eight CD7+ CD56+ myeloid/natural killer cell precursor acute leukemias) by flow cytometry. In AML, 38 samples were positive for moab 7.1 ('20%-cut-off-level'). These moab 7.1-positive AML cases revealed a myelomonocytic-differentiated immunophenotype with coexpression of the NK cell marker CD56 in 33 of 38 cases. Two of eight cell samples of the recently described CD7+ CD56+ myeloid/natural killer cell precursor acute leukemia entity reacted with moab 7.1. In ALL, 35 samples mostly of the pro-B-ALL subtype (33 pro-B-ALL, one common-ALL, one pre-B-ALL) were positive for moab 7.1. 58 (81%) of 72 samples with MLL rearrangements were positive for moab 7.1 including 28/31 with a t(4;11), 16/17 with a t(9;11), 3/5 with a t(11;19), and 2/6 with a del(11)(q23). All moab 7.1-positive ALL (n = 34) and childhood AML (n = 17) cases revealed MLL rearrangements as detected by Southern blot analysis and RT-PCR. However, 11 adults with AML, and one adult with moab 7.1-positive CD7+ CD56+ myeloid/natural killer cell precursor acute leukemia were negative for MLL rearrangements as proved by Southern blot analysis. We conclude that moab 7.1 is a sensitive but not entirely specific marker for the identification of 11q23-associated AML and ALL by flow cytometry in children and adults.
Leukemia 2000 Jul
PMID:Detection of acute leukemia cells with mixed lineage leukemia (MLL) gene rearrangements by flow cytometry using monoclonal antibody 7.1. 1091 47

Certain glycosaminoglycans (GAGs), including heparin, inhibit infection by murine leukemia virus (MLV). We now show that this is due to inhibition of virus attachment independent of the interaction between viral envelope proteins (Env) and their cellular receptors. Heparin blocked the binding of both Env-deficient and amphotropic MLV (MLV-A) particles to NIH 3T3 fibroblasts, CHO cells which lack the amphotropic retroviral receptor Pit-2, and CHO cells transfected with Pit-2 (CHO-Pit-2). Heparin also inhibited the transduction of NIH 3T3 cells by MLV-A over a similar concentration range. This effect was observed within 15 min of exposure to retrovirus. Preloading target cells with heparin had no effect on transduction and both MLV-A and Env-deficient retrovirus bound efficiently to heparin-coated agarose beads, suggesting that heparin interacts with the virus rather than the target cell. This requires both a strong negative charge and a specific structure since GAGs with different charge and carbohydrate composition inhibited virus infection variably. The specificity of GAG-virus interaction also depends on the producer cells, since virus packaged by murine GP+EnvAM12 cells was 1,000-fold more sensitive to inhibition by chondroitin sulfate A than was virus packaged by human FLYA13 packaging cells. No evidence for an interaction between MLV and cell surface proteoglycans was found, however, since the attachment of MLV-A and envelope-defective virus to proteoglycan-deficient CHOpgsA-745 cells was similar to that seen with both wild-type and CHO-Pit-2 cells. Although the molecular mechanism is unclear, this study presents evidence that Env receptor-independent attachment is an important step in MLV infection.
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PMID:Heparin binds to murine leukemia virus and inhibits Env-independent attachment and infection. 1207 92

The expression of the chondroitin sulfate proteoglycan neuron-glial antigen 2 (NG2) has been demonstrated in association with rearrangement of the mixed lineage leukemia (MLL) gene in acute leukemia, but the frequency of NG2 expression in adult acute lymphoblastic leukemia (ALL) is yet unknown. We evaluated NG2 expression in 313 adult ALL patients by flow cytometry and simultaneously determined MLL rearrangement in 120 adult patients out of them with B-precursor ALL by reverse transcription-polymerase chain reaction and fluorescence in situ hybridization. A total of 57% of pro-B ALL, 2% of common ALL and 20% of pre-B ALL were NG2 positive, but NG2 was absent in T-ALL and mature B-ALL. In B-precursor ALL, NG2 expression was significantly associated with a CD10(-)/CD34(-)/CD24(-)/CD65s(+)/CD15(+)/CD13(-)/CD33(-) phenotype and showed a sensitivity, specificity and positive predictive value of 0.89, 0.89, and 0.93 for MLL rearrangement, respectively. NG2 was positive in three patients without detectable MLL rearrangement and negative in eight patients with MLL-AF4 transcripts. However, NG2 predicted with a 100% accuracy MLL rearrangement among patients disclosing a CD65s(+) and/or CD15(+) immunophenotype. In summary, NG2 adds to a more precise identification of high-risk adult ALL and should therefore be included into diagnostic marker panels. As NG2 is negative in non-malignant hematopoietic cells, this novel antigen might also serve in future studies as a powerful marker in monitoring minimal residual disease.
Leukemia 2003 Aug
PMID:Expression of the human homologue of rat NG2 in adult acute lymphoblastic leukemia: close association with MLL rearrangement and a CD10(-)/CD24(-)/CD65s(+)/CD15(+) B-cell phenotype. 1288 47

Pre-B cell leukemia transcription factors (PBXs) act as cofactors in the transcriptional regulation mediated by Homeobox proteins during embryonic development and cellular differentition. PBX1 protein is expressed throughout murine embryonic development, and its deletion in mice disrupts chondrogenesis. PBX protein levels are also increased in mouse embryonal carcinoma P19 cells during retinoic acid (RA)-induced differentiation. To elucidate the role of PBX proteins in this process, we stably overexpressed PBX1b antisense mRNA in P19 cells (PBX1b-AS cells). PBX1b-AS cells did not differentiate to neuronal or endodermal cells following treatment with RA suggesting PBX proteins are required for both processes. Furthermore we demonstrated that PBX proteins regulate the RA-dependent induction in the mRNA levels of bone morphogenetic protein 4 (BMP4) and Decorin (DCN) in P19 cells using both PBX1b-AS cells and PBX1 small interfering RNA. Chromatin immunoprecipitation assays further demonstrated that PBX proteins directly bind to the promoter of Bmp4 and Dcn in vivo in a RA-dependent fashion. In addition, type I and type II BMP receptor mRNA levels were also increased in P19 cells following RA treatment; however, this was PBX-independent. Taken together these data demonstrate that PBX proteins are required for RA-induced differentiation of P19 cells and that PBX proteins regulate the expression of BMP4 and DCN during this differentiation process.
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PMID:Pre-B cell leukemia transcription factor (PBX) proteins are important mediators for retinoic acid-dependent endodermal and neuronal differentiation of mouse embryonal carcinoma P19 cells. 1474 27

Target cell entry of murine leukaemia virus vectors proceeds via primary attachment, independent of the viral envelope protein and subsequent envelope-receptor interaction. Although much attention has been paid to modifying the latter for target cell specificity, the initial binding interaction has been overlooked, despite its opposing involvement both in providing the virus available for receptor binding and in depleting free virus. As a first step towards modifying primary attachment, both to provide specificity and to enhance vector availability, we sought to determine the nature of this interaction. Following an initial screen of GAGs (glycosaminoglycans) for their ability to inhibit virus binding and transduction, we have shown that production of virus from cells in which GAG sulfation is inhibited, or treatment of virus with heparinase III, reduces both particle attachment and infection. Detection in purified virus preparations of a neo-epitope generated by heparinase III confirmed the presence of virus-associated HSPG [HS (heparan sulfate) proteoglycan], acquired from the producer cell. We propose that host-acquired cell-surface HSPG (potentially including syndecan-2) provides a means of virus attachment to target cells that precedes specific receptor interaction and membrane fusion. Inhibition of HS biosynthesis may provide a sufficiently reduced background of primary binding such that novel mechanisms of attachment, ideally with appropriate target cell specificity, can be introduced.
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PMID:Primary attachment of murine leukaemia virus vector mediated by particle-associated heparan sulfate proteoglycan. 1689 23

Serglycin is the major cell-associated proteoglycan of hematopoietic cells. Previous work has demonstrated that serglycin may be involved in targeting some proteins to granules of cytotoxic lymphocytes, mast cells and neutrophils. We characterized the expression of serglycin in various hematologic malignancies by immunohistochemistry and ELISA. Serglycin expression was found to distinguish acute myeloid leukemia (AML) from acute lymphoblastic leukemia. In contrast to myeloperoxidase, serglycin was found to be a selective marker for immature myeloid cells, distinguishing AML from Philadelphia chromosome-negative chronic myeloproliferative disorders.
Leukemia 2007 Dec
PMID:Serglycin proteoglycan in hematologic malignancies: a marker of acute myeloid leukemia. 1792 83

We have previously reported that r28M, a recombinant bispecific single-chain antibody directed to a melanoma-associated proteoglycan (NG2) and the costimulatory CD28 molecule on T cells, induced T-cell activation, which resulted in tumor-cell killing. T-cell activation did not require a primary signal through the T-cell antigen receptor (TCR)/CD3 complex and depended on the presence of NG2-positive tumor cells. Here, we further investigate this phenomenon of a target cell-restricted, supra-agonistic CD28 stimulation with bispecific antibodies. To this end, we exchanged the NG2 targeting part of r28M with a single-chain antibody directed to the B-cell associated antigen CD20. The resulting bispecific single-chain antibody, termed r2820, induced supra-agonistic T-cell activation, which required the presence of autologous normal or malignant B cells, respectively. Once activated, T cells were capable of destroying lymphoma target cells.These findings demonstrate that supra-agonistic CD28 stimulation with bispecific single-chain antibodies is a robust and readily reproducible phenomenon. In the context of experimental tumor therapy, it may provide a valuable alternative to the unrestricted T-cell activation induced by 'super-agonistic', monospecific CD28 antibodies.
Leukemia 2009 Jan
PMID:A bispecific single-chain antibody that mediates target cell-restricted, supra-agonistic CD28 stimulation and killing of lymphoma cells. 1883 Feb 57


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