UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have purified a 30-kDa serine protease (designated RNK-Met-1) from the granules of the rat large granular lymphocyte leukemia cell line (RNK-16) that hydrolytically cleaves model peptide substrates after methionine, leucine, and norleucine (Met-ase activity). Utilizing molecular sieve chromatography, heparin-agarose, chromatography, and reverse-phase high pressure liquid chromatography, RNK-Met-1 was purified to homogeneity and 25 NH2-terminal amino acids were sequenced. By using the polymerase chain reaction, oligonucleotide primers derived from amino acids at position 14-25 and from a downstream active site conserved in other serine protease genes were used to generate a 534-base pair cDNA clone encoding a novel serine protease from RNK-16 mRNA. This cDNA clone was used to isolate a full-length 867-base pair RNK-Met-1 cDNA from an RNK-16 lambda-gt11 library. The open reading frame predicts a mature protein of 238 amino acids with two potential sites for N-linked glycosylation. The cDNA also encodes a leader peptide of at least 20 amino acids. The characteristic Ile-Ile-Gly-Gly amino acids of the NH2 terminus and the His, Asp, and Ser residues that form the catalytic triad of serine proteases were both conserved. The amino acid sequence has less than 45% identity with any other member of the serine protease family, indicating that RNK-Met-1 is distinct and may itself represent a new subfamily of serine proteases. Northern blot analysis of total cellular RNA detected a single 0.9-kilobase mRNA in the in vitro and in vivo variants of RNK-16 and in spleen-derived plastic-adherent rat lymphokine-activated killer cells. RNK-Met-1 mRNA was not detectable in freshly isolated rat splenocytes, thymocytes, brain, colon, and liver or activated nonadherent rat splenocytes and thymocytes. These data indicate that RNK-Met-1 is a serine protease with unique activity that is expressed in the granules of large granular lymphocytes.
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PMID:Purification and cloning of a novel serine protease, RNK-Met-1, from the granules of a rat natural killer cell leukemia. 144 89

Rat natural killer cell Met-ase-1 (RNK-Met-1) is a 30,000 M(r) serine protease (granzyme) found in the cytolytic granules of CD3- large granular lymphocytes (LGL) with natural killer (NK) activity. To characterize the genomic sequences responsible for the CD3- LGL-restricted expression of this gene, we screened a rat genomic library with RNK-Met-1 cDNA, and obtained bacteriophage clones that contained the RNK-Met-1 gene. The RNK-Met-1 gene comprises 5 exons and spans approximately 5.2 kilobases (kb), exhibiting a similar structural organization to a class of CTL-serine proteases with protease catalytic residues encoded near the borders of exons 2, 3, and 5. The 5'-flanking region of the RNK-Met-1 gene contains a number of putative promoter and enhancer regulatory elements and shares several regions of homology with the 5'-flanking region of the mouse perforin gene. We have prepared nested deletions from approximately 3.3 kb of the 5'-flanking region of the RNK-Met-1 gene, and inserted these upstream of the chloramphenicol acetyltransferase (CAT) reporter gene. These 5'-flanking RNK-Met-1-CAT constructs were transiently transfected into rat LGL leukemia, T-lymphoma, and basophilic leukemia cell lines. The transcriptional activity of the RNK-Met-1 5'-flanking region was strong, restricted to the RNK-16 LGL leukemia and controlled by several positive cis-acting regions spread over at least 3.3 kb. The longest and most active 5'-flanking region (-3341 to -33) was also used to drive specific expression of beta-galactosidase in RNK-16. These data are consistent with the NK cell-specific expression of RNK-Met-1 and suggest the potential utility of this gene promoter in the development of transgene models of NK cell biology in vivo.
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PMID:Cloning and characterization of a novel NK cell-specific serine protease gene and its functional 5'-flanking sequences. 760 1

A cDNA clone encoding a human NK serine protease was obtained by screening a lambda-gt10 library from the Lopez NK leukemia with the rat natural killer Met-ase (RNK-Met-1) cDNA clone. In Northern blot analysis human Met-ase (Hu-Met-1) cDNA hybridized with a 0.9-kb mRNA in two human NK leukemia cell lines, unstimulated human PBMC, and untreated purified CD3-CD56+ large granular lymphocytes. Unlike other members of the granzyme family that are highly expressed in activated peripheral T cells, the Hu-Met-1 transcript was barely detected in a population of PMA and ionomycin or IL-2-treated high density T cells. Several in vitro cultured Burkitt lymphomas, chronic- and promyeloid leukemias, acute lymphoblastic leukemias, and colon and ovarian carcinomas and colon and ovarian carcinomas did not express Hu-Met-1 mRNA. Hu-Met-1 mRNA expression in a small number of human T cell tumor lines did not correlate with any particular phenotype or stage of development. The presence of Hu-Met-1 mRNA closely correlated with the Met-ase activity of cellular lysates prepared from these various human peripheral blood subsets and in vitro cultured cell lines. Met-ase activity detected in whole cell lysates of cytotoxic lymphocytes was associated with the cytoplasmic granules of these cells. The nucleotide sequence of the Hu-Met-1 cDNA clone encodes a predicted serine protease of 257 amino acids. The predicted protein is an active enzyme of 232 amino acids with a calculated unglycosylated m.w. of 27,100. Hu-Met-1 is 66% identical to RNK-Met-1 at the amino acid level. The human and rat mature protein sequences conserve the active site His, Asp, and Ser amino acids that form the catalytic triad of serine proteases, all 8 cysteine residues, and several amino acids critical in the formation of the substrate binding pocket. The gene for the Hu-Met-1 serine protease is located on chromosome 19, which distinguishes it from any other member of the human granzyme family.
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PMID:Met-ase: cloning and distinct chromosomal location of a serine protease preferentially expressed in human natural killer cells. 824 61

Met-ase-1 is a 30 000 Mr serine protease (granzyme) that was first isolated in the cytolytic granules of rat CD3(-) large granular lymphocytes. We screened a mouse genomic library with rat Met-ase-1 cDNA, and obtained bacteriophage clones that contained the mouse Met-ase-1 gene. The mouse Met-ase-1 gene comprises five exons spanning approximately 5.2 kilobases (kb) and exhibits a similar structural organization to its rat homologue and a family of neutrophil elastase-like serine proteases. Mouse Met-ase-1 mRNA was only detected in total cellular and poly A mRNA of mouse CD3(-) GM1(+) large granular lymphocytes derived from splenocytes stimulated with IL-2 and the mouse NK1.1(+) cell line 4 - 16. Spleen T-cell populations generated by Concanavalin A stimulation and a number of mouse pre-NK and T cell lines did not express mouse Met-ase-1 mRNA. The 5' flanking region of the mouse Met-ase-1 gene also shares considerable regions of identity with the 5' flanking region of the rat Met-ase-1 gene. A 3.3 kb segment of 5' sequence flanking the mouse Met-ase-1 gene was inserted upstream of the chloramphenicol acetyltransferase reporter gene and this construct transiently transfected into a variety of mouse and rat large granular lymphocyte leukemia and T-cell lines. The transcriptional activity of the mouse Met-ase-1 5' flanking region was significant in the RNK-16 large granular lymphocyte leukemia, strongest in the 4 - 16 mouse NK1.1(+) cell line, and weak in several mouse pre-NK cell lines. Reverse transcriptase polymerase chain reaction of mouse large granular lymphocyte mRNA was used to derive the full-length coding sequence for mouse Met-ase-1. The predicted hexapropeptide of mouse Met-ase-1 (Asn-6 to Gln-1), was deleted by polymerase chain reaction mutagenesis to enable expression of active mouse Met-ase-1 in mammalian COS-7 cells. Northern blot analysis and protease assays of transfected COS cell lysates against a panel of thiobenzyl ester substrates formally demonstrated that the mouse Met-ase-1 gene encodes a serine proteinase that hydrolyzes substrates containing a long narrow hydrophobic amino acids like methionine, norleucine, and leucine in the P1.
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PMID:Cloning and expression of the recombinant mouse natural killer cell granzyme Met-ase-1. 878 Nov 19

Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell lymphotrophic virus-I infected individuals. The leukemia consists of an overabundance of activated T cells, which are characterized by the expression of CD25, or IL-2Ralpha, on their cell surface. Presently, there is not an accepted curative therapy for ATL. We developed an in vivo model of ATL in non-obese diabetic/severe combined immunodeficient (NOD/ SCID) mice by introducing cells from an ATL patient (MET-1) into the mice. The leukemic cells proliferated in these mice that lack functional T, B, and natural killer (NK) cells. The MET-1 leukemic cells could be monitored by measurements of both serum soluble Tac (IL-2Ralpha) and soluble human beta2-microglobulin (beta2mu) by ELISA. The disease progressed to death in the mice after approximately 4-6 weeks. The mice developed grossly enlarged spleens and a leukemia involving ATL cells that retained the phenotype and the T-cell receptor rearrangement and human T-cell lymphotrophic virus-I integration pattern of the patient's ATL leukemia cells. This model is of value for testing the efficacy of novel therapeutic agents for ATL. The administration of humanized anti-Tac (HAT), murine anti-Tac (MAT), and 7G7/B6, all of which target IL-2Ralpha, significantly delayed the progression of the leukemia and prolonged the survival of the tumor-bearing mice. In particular, HAT induced complete remissions in 4 of 19 mice and partial remissions in the remainder. It appears that the antibodies act by a mechanism that had not been anticipated. The prevailing view is that antibodies to the IL-2Ralpha receptor have their effective action by blocking the interaction of IL-2 with its growth factor receptor, thereby inducing cytokine deprivation apoptosis. However, although both HAT and MAT block the binding of IL-2 to IL-2Ralpha of the high affinity receptor, the 7G7/B6 monoclonal antibody binds to a different epitope on the IL-2Ralpha receptor, one that is not involved in IL-2 binding. This suggested that the antibodies provide an effective therapy by a mechanism other than induction of cytokine deprivation. In accord with this view, the MET-1 cells obtained from the spleens of leukemic mice did not produce IL-2, nor did they express IL-2 mRNA as assessed by reverse transcription-PCR. Another possible conventional mechanism of action involves complement-mediated killing. However, although MAT and 7G7/B6 fix rabbit complement, HAT does not do so. Furthermore, in the presence of NOD/SCID mouse serum, there was no complement-mediated lysis of MET-1 cells. In addition, the antibodies did not manifest antibody-dependent cellular cytotoxicity with NOD/SCID splenocytes that virtually lack NK cells as the effector cells as assessed in an in vitro chromium-release assay. However, in contrast to the efficacy of intact HAT, the F(ab')2 version of this antibody was not effective in prolonging the survival of mice injected with MET-1 ATL cells. In conclusion, in our murine model of ATL, monoclonal antibodies, HAT, MAT, and 7G7/B6, appear to delay progression of the leukemia by a mechanism of action that is different from the accepted mechanism of IL-2 deprivation leading to cell death. We consider two alternatives: the first, antibody-dependent cellular cytotoxicity mediated by FcRI- or FcRIII-expressing cells other than NK cells, such as monocytes or polymorphonuclear leukocytes. The second alternative we consider involves direct induction of apoptosis by the anti-IL-2R antibodies in vivo. It has been shown that the IL-2R is a critical element in the peripheral self-tolerance T-cell suicide mechanism involved in the phenomenon of activation-induced cell death.
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PMID:IL-2Ralpha-Directed monoclonal antibodies provide effective therapy in a murine model of adult T-cell leukemia by a mechanism other than blockade of IL-2/IL-2Ralpha interaction. 1115 99

Adult T-cell leukemia (ATL) develops in a small proportion of human T-cell leukemia virus I-infected individuals. Presently, there is no effective therapy for ATL. A murine model of ATL was produced by introducing leukemic cells (MET-1) from an ATL patient into nonobese diabetic/severe combined immunodeficient mice. The MET-1 cells are activated T cells that express CD2, CD3, CD4, CD25, CD122, and CD52. We evaluated the efficacy of Campath-1H (alemtuzumab; a humanized monoclonal antibody directed to CD52), alone and in combination with humanized anti-Tac (HAT) directed to CD25 (interleukin 2 receptor alpha) or with MEDI-507 directed to CD2. We observed that four weekly treatments with 4 mg/kg HAT significantly prolonged survival of MET-1-bearing mice. However, the survival of mice receiving 4 weeks of 4 mg/kg Campath-1H was significantly longer than that of the group receiving four weekly treatments with HAT (P < 0.001). Treatment with Campath-1H for 4 weeks led to a striking prolongation of the survival of MET-1 ATL-bearing mice that was comparable with that of tumor-free nontreated controls. Using Fc receptor (FcR) gamma(-/-) mice, we found that FcRgammas on polymorphonuclear leukocytes and monocytes are required for Campath-1H-mediated tumor killing in vivo. These results demonstrate that Campath-1H has therapeutic efficacy on ATL in vivo in that the life span of the Campath-1H treatment group was comparable with that of mice that did not receive a tumor or therapy. The main tumor killing mechanism with Campath-1H in vivo involves FcRgamma-containing receptors (e.g., FcRgammaIII) on polymorphonuclear leukocytes and macrophages that mediate antibody-dependent cellular cytotoxicity and/or trigger cross-linking induced apoptosis. This study provides support for a clinical trial of Campath-1H in the treatment of patients with T-cell leukemias and lymphomas.
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PMID:Effective therapy for a murine model of adult T-cell leukemia with the humanized anti-CD52 monoclonal antibody, Campath-1H. 1455 36

We previously showed therapeutic efficacy of humanized anti-Tac (HAT), murine anti-Tac (MAT), and 7G7/B6 monoclonal antibodies, which recognize CD25, for human adult T-cell leukemia (ATL) in a murine model. In this study, we investigated the mechanism underlying the tumor-killing action mediated by these antibodies on an ATL model in nonobese diabetic/severe combined immunodeficient (SCID/NOD) wild-type mice that lack effective T and natural killer (NK) cells and in SCID/NOD Fc receptor common gamma chain knockout (FcRgamma-/-) mice. The ATL model was established by i.p. injection of human ATL cells (MET-1) into SCID/NOD wild-type or SCID/NOD FcRgamma-/- mice. HAT, MAT, and 7G7/B6 were given to the leukemia-bearing mice at a dose of 100 microg weekly for 4 weeks. The three antibodies inhibited the leukemia growth significantly in SCID/NOD wild-type mice, as monitored by serum levels of human beta2-microglobulin (P < 0.01), and prolonged survival of the leukemia-bearing SCID/NOD wild-type mice (P < 0.01) as compared with the control group. However, none of the antibodies manifested efficacy on the leukemia growth and survival of the SCID/NOD FcRgamma-/- mice bearing MET-1 leukemia. In a pharmacokinetics study, the blood concentrations of the radiolabeled antibodies decreased with time similarly in SCID/NOD wild-type and SCID/NOD FcRgamma-/- mice. Although NK cells may play a role in humans, in this murine model FcRgamma receptors on non-NK cells, such as polymorphonuclear leukocytes or monocytes, are required for the tumor-killing action of the antibodies directed toward CD25.
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PMID:Activating Fc receptors are required for antitumor efficacy of the antibodies directed toward CD25 in a murine model of adult t-cell leukemia. 1531 26

Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1. The leukemia consists of an overabundance of activated T cells, which express CD25 on their cell surfaces. Presently, there is no accepted curative therapy for ATL. Flavopiridol, an inhibitor of cyclin-dependent kinases, has potent antiproliferative effects and antitumor activity. We investigated the therapeutic efficacy of flavopiridol alone and in combination with humanized anti-Tac antibody (HAT), which recognizes CD25, in a murine model of human ATL. The ATL model was established by intraperitoneal injection of MET-1 leukemic cells into nonobese diabetic/severe combined immunodeficient mice. Either flavopiridol, given 2.5 mg/kg body weight daily for 5 days, or HAT, given 100 microg weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of human beta-2-microglobulin (beta2mu; P < .01), and prolonged survival of the leukemia-bearing mice (P < .05) as compared with the control group. Combination of the 2 agents dramatically enhanced the antitumor effect, as shown by both beta2mu levels and survival of the mice, when compared with those in the flavopiridol or HAT alone group (P < .01). The significantly improved therapeutic efficacy by combining flavopiridol with HAT provides support for a clinical trial in the treatment of ATL.
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PMID:Combination therapy for adult T-cell leukemia-xenografted mice: flavopiridol and anti-CD25 monoclonal antibody. 1538 55

Adult T-cell leukemia (ATL) consists of an overabundance of T cells, which express CD25. Therapeutic efficacy of astatine-211 ((211)At)-labeled murine monoclonal antibody 7G7/B6 alone and in combination with daclizumab was evaluated in nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice given injections of MET-1 human T-cell leukemia cells. Daclizumab and 7G7/B6 are directed toward different epitopes of CD25. Either a single dose of 12 microCi (0.444 MBq) (211)At-7G7/B6 per mouse given intravenously or receptor-saturating doses of daclizumab given at 100 microg weekly for 4 weeks intravenously inhibited tumor growth as monitored by serum levels of human beta-2 microglobulin (beta(2)mu) and by prolonged survival of leukemia-bearing mice compared with the control groups (P < .001). The combination of 2 agents enhanced the antitumor effect when compared with groups treated with 12 microCi (0.444 MBq) of (211)At-7G7/B6 (P < .05) or daclizumab alone (P < .05). The median survival duration of the PBS group was 62.6 days and 61.5 days in the radiolabeled nonspecific antibody (211)At-11F11-treated group. In contrast, 91% of mice in the combination group survived through day 94. These results that demonstrate a significantly improved therapeutic efficacy by combining (211)At-7G7/B6 with daclizumab support a clinical trial of this regimen in patients with ATL.
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PMID:Effective treatment of a murine model of adult T-cell leukemia using 211At-7G7/B6 and its combination with unmodified anti-Tac (daclizumab) directed toward CD25. 1656 69

Infection with human T-cell leukemia virus type 1 (HTLV-1) leads sometimes to the development of adult T-cell lymphoma/leukemia (ATL), which is invariably fatal and often associated with humoral hypercalcemia of malignancy. The transformation of infected CD4 T cells and the pathogenesis of leukemia have been studied with great limitation in tissue culture and patients. To better understand the pathogenesis and perform preclinical drug studies, animal models of ATL are urgently needed. In mice, inoculation of HTLV-1 cell lines mostly leads to development of localized lymphomas. To develop an ATL animal model with leukemic spread of ATL cells, mouse strains with different well-defined immune deficiencies were inoculated intraperitoneally with different HTLV-1-infected cell lines (ACH.2, C8166, MT-2, MET-1). Inoculation of MET-1 cells into NOD/SCID mice provided the best model system for slowly developing T-cell leukemia with multiple organ involvement. In leukemic mice, an increase in serum calcium levels correlated with expression of receptor activator of nuclear factor kappa-light-chain-enhancer of activated B cells ligand on leukemic cells and secretion of parathyroid hormone-related protein and interleukin-6. In contrast to the other cell lines that did not spread systemically, MET-1 expressed both the adhesion molecules CD11a (LFA-1alpha) and CD49d (VLA-4alpha) and produced or induced expression of matrix metalloproteinases 1, 2, 3, and 9, thus underlining the importance of these molecules in the spread of adult T-cell leukemia cells. The MET-1/NOD/SCID model will be useful for developing interventions against invasion and spread of leukemic cells and subsequent humoral hypercalcemia of malignancy.
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PMID:Expression of tumor invasion factors determines systemic engraftment and induction of humoral hypercalcemia in a mouse model of adult T-cell leukemia. 1942 77

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