Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Circulating blood plasma contains proteinase-degraded forms of thrombomodulin that are soluble. We quantitatively assayed the plasma levels of thrombomodulin in 15 patients with chronic myelogenous leukemia (CML) in chronic phase by method of an enzyme-linked immunosorbent assay using a monoclonal antibody to protease-degraded products of thrombomodulin. Plasma levels of thrombomodulin in patients with CML at diagnosis were significantly increased (19.5 +/- 6.2 ng/ml: means +/- SD) compared with the levels in normal controls (8.0 +/- 1.9 ng/ml, n = 20) (P less than 0.001). Fibrin degradation products (D-dimer), thrombin-antithrombin III complex, and plasmin alpha 2-antiplasmin complex were almost normal, suggesting that intravascular coagulation or plasmin-mediated fibrinolysis little occurred in these patients. On the other hand, the plasma levels of elastase-alpha 1-proteinase inhibitor (E-alpha 1PI) complex, which was the indicator of released leukocyte elastase, were significantly increased in CML (P less than 0.0001). The plasma levels of thrombomodulin and E-alpha 1PI complex were decreased in parallel with decline of leukocyte counts in 10 patients with CML following anti-leukemic therapy. Furthermore, a statistically significant correlation was observed between the plasma levels of thrombomodulin and E-alpha 1PI complex obtained at 39 time points in 15 patients with CML (r = 0.81, P less than 0.001). These results suggest that the increased plasma levels of thrombomodulin in CML may be partly caused by leukocyte elastase, which may split the surface thrombomodulin and release protease-degraded fragments of it into the circulation.
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PMID:Increased levels of plasma thrombomodulin in chronic myelogenous leukemia. 131 1

An antiserum to human cathepsin G has been raised in sheep and its reactivity with human tissues has been tested. The indirect immunoperoxidase staining sequence was employed and was applied to routinely processed paraffin sections. Mature granulocytes, especially those of the neutrophil variety, were intensely and consistently stained. Activity was not observed in other cell or tissue types. Many of the cells of acute and chronic myeloid leukemia were strongly stained, in contrast to those of acute lymphoblastic or chronic lymphocytic leukemias. The results of the technique are compared with those described with staining for muramidase (lysozyme), alpha 1-antitrypsin, leukocyte elastase, and naphthol-AS-D-chloroacetate esterase, and with certain monoclonal antisera directed against granulocyte determinants.
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PMID:Immunohistochemical localization of cathepsin G in human tissues. 391 78

Early chronic myeloid leukemia (CML) and leukemoid reaction (LR) sometimes show similar histological pictures. In order to assess the efficacy of immunohistochemistry in the discrimination of the two forms, twenty bone marrow (BM) trephines of patient with CML and twenty with LR were immunostained and studied. A wide spectrum of antibodies effective on paraffin-embedded tissues (NP 57 anti-neutrophil elastase, Leu M1, MAC 387, KP1, Y2/51, LCA, UCHL1, L26, BerH2 and Glycophorin A) and directed against granulopoietic, erythropoietic, megakaryocytic, monocytic and lymphoid cells was tested by means of the alkaline phosphatase anti-alkaline phosphatase (APAAP) method. Expression of neutrophil elastase in CML and LR showed a different pattern of reactivity in normal and neoplastic granulocytic cells and Y2/51 put in evidence significant discrepancies of megakaryocytes in the two groups. Moreover, a greater number of histiocytic, lymphoid and erythropoietic cells were detected in LR after immunostaining with KP1, LCA, UCHL1, L26 and Glycophorin A. The different immunophenotypical pictures observed, suggest the value of immunohistochemistry as a supplementary diagnostic tool for the differential diagnosis between early CML and LR.
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PMID:[Immunophenotyping of early-phase chronic myeloid leukemia and leukemoid reaction]. 770 38

Proteinase 3 (PR3) is one of four serine protease homologues in the azurophilic granules of neutrophils and granules of monocytes. It is of importance that anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG) are mainly directed against PR3 only. Furthermore, PR3 is overexpressed in a variety of acute and chronic myeloid leukemia cells. Cytotoxic T lymphocytes specific for a PR3-derived peptide have been shown to specifically lyse leukemia cells that overexpress PR3. This review will focus on PR3 and the characteristics of PR3 that might implicate this particular antigen in the pathogenesis of WG and as target for immunotherapy in myeloid leukemias. We will discuss the genetic localization and gene regulation of PR3, the processing, storage, and expression of the PR3 protein, and the physiological functions of PR3, and compare this with the three other neutrophil-derived serine proteases: human leukocyte elastase, cathepsin G, and azurocidin. Three main differences are described between PR3 and the other serine proteases. This makes PR3 a very intriguing protein with a large array of physiological functions, some of which may play a role in ANCA-associated vasculitidis and myeloid leukemia.
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PMID:Proteinase 3, Wegener's autoantigen: from gene to antigen. 1127 67

Clinical observations suggest that in chronic myelogenous leukemia (CML), the Philadelphia chromosome (Ph+) clone has a growth advantage over normal hematopoiesis. Patients with CML have high levels of neutrophil elastase, which has recently been shown to antagonize the action of granulocyte-colony-stimulating factor (G-CSF) and other growth factors. We therefore compared the effect of elastase on the growth of normal and CML progenitor cells. In 10-day suspension cultures of normal or CML CD34+ cells supplemented with G-CSF, stem cell factor (SCF), and granulocyte macrophage-colony-stimulating factor (GM-CSF), CML cells had diminished sensitivity to the growth inhibitory effect of elastase. When equal numbers of CML and normal CD34+ cells were cocultured for 10 days, there was no change in the relative proportions of normal and leukemic cells (measured by fluorescence in situ hybridization [FISH] or flow cytometry). However, when elastase was added, CML cells predominated at the end of the culture period (78% vs 22% with 1 microg/mL and 80% vs 20% with 5 microg/mL elastase). CML neutrophils substituted effectively for elastase in suppressing the proliferation of normal CD34+ cells, but this effect was abrogated by serine protease inhibitors. These results suggest that elastase overproduction by the leukemic clone can change the growth environment by digesting growth factors, thereby giving advantage to Ph+ hematopoiesis.
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PMID:Clonal dominance of chronic myelogenous leukemia is associated with diminished sensitivity to the antiproliferative effects of neutrophil elastase. 1289 59

Human neutrophil elastase (HNE) and proteinase 3 (PRO3) are myeloid tissue-restricted serine proteases, aberrantly expressed by myeloid leukemia cells. PRO3 and HNE share the PR1 peptide sequence that induces HLA-A*0201-restricted cytotoxic T cells (CTLs) with antileukemia reactivity. We studied the entire HNE protein for its ability to induce CTLs. In an 18-hour culture, HNE-loaded monocytes stimulated significant intracellular interferon gamma (IFN-gamma) production by CD4+ and CD8+ T cells in 12 of 20 and 8 of 20 healthy individuals, respectively. Lymphocytes from 2 HNE responders were pulsed weekly for 4 weeks to generate HNE-specific CTLs. One of 2 HLA-A*0201-negative individuals inhibited the colony formation of HLA-identical chronic myelogenous leukemia progenitor cells (73% inhibition at 50:1 effector-target [E/T] ratio), indicating that peptides other than PR1 can induce leukemia-reactive CTLs. Repetitive stimulations with HNE in 2 of 5 HLA-A*0201+ individuals increased PR1 tetramer-positive CD8+ T-cell frequencies from 0.1% to 0.29% and 0.02% to 0.55%, respectively. These CTLs recognized PR1 peptide or killed HNE-loaded targets. These results indicate that exogenously processed HNE is a source of PR1 peptide as well as other peptide sequences capable of inducing leukemia-specific CD8+ and CD4+ T cells. HNE could, therefore, be used in an HLA-unrestricted manner to induce leukemia-reactive CTLs for adoptive immunotherapy.
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PMID:Identification and in vitro expansion of CD4+ and CD8+ T cells specific for human neutrophil elastase. 1507 Jun 88

Renal involvement by leukemic cells is rare in chronic myelogenous leukemia (CML). Herein, this study reports a case of CML associated with renal involvement of leukemic cells, which occurred 1 and 1/2 years after the initial diagnosis. Abdomino-pelvic computed tomography revealed a 4.4 x 4.2 cm-sized, low-density solid mass having a thick wall from the mid to lower pole of the left kidney. A peripheral blood analysis revealed blastic transformation of CML. The biopsied renal parenchyme was diffusely infiltrated by sheets of immature myeloid cells, polymorphonuclear leukocytes, and occasional eosinophils. Most of the infiltrating cells were positive for anti-neutrophil elastase, but negative for lymphoid markers. Therefore, differential diagnosis of a kidney tumor during the course of CML, especially in the time of blastic transformation, should be performed.
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PMID:Renal involvement of chronic myelogenous leukemia presenting as a kidney tumor. 1551 10

The primary granule proteins (PGP) of myeloid cells are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. Therefore, we developed a method to induce T-cell responses to PGP protein sequences. We found that gene-transfected antigen-presenting cells efficiently expand functionally competent PGP-specific CD4 and CD8 T cells. The system was optimized using T-cell responses to autologous CD40-activated B cells (CD40-B) transfected with a cytomegalovirus pp65-encoding expression vector. To generate leukemia-specific T cells, expression vectors encoding the PGP proteinase 3 (PR3), human neutrophil elastase, and cathepsin-G were transfected into CD40-B cells to stimulate post-allogeneic stem cell transplantation T cells from five patients with myeloid and three with lymphoid leukemias. T-cell responses to PGP proteinase 3 and human neutrophil elastase were observed in CD8+ and CD4+ T cells only in patients with myeloid leukemias. T-cell responses against cathepsin-G occurred in both myeloid and lymphoblastic leukemias. T cells from a patient with chronic myelogenous leukemia (CML) and from a posttransplant CML patient, expanded against PGP, produced IFN-gamma or were cytotoxic to the patient's CML cells, demonstrating specific antileukemic efficacy. This study emphasizes the clinical potential of PGP for expansion and adoptive transfer of polyclonal leukemia antigen-specific T cells to treat leukemia.
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PMID:In vitro induction of myeloid leukemia-specific CD4 and CD8 T cells by CD40 ligand-activated B cells gene modified to express primary granule proteins. 1595 35

The graft-versus-leukemia (GVL) effect following allogeneic stem cell transplantation is testament to the effectiveness of the immune system in recognizing and eliminating leukemia cells. The successful identification of a range of leukemia-associated antigens (LAAs) that drive the GVL response in recent years has stimulated research in the development of vaccines to treat hematological malignancies. Here, we review the current experience with the PR1 vaccine. PR1 is a nine amino acid, HLA-A(*)0201-restricted peptide, shared by two myeloid LAAs, proteinase (PR)3 and neutrophil elastase (NE). PR3 and NE are found in the primary (azurophil) granule proteins of normal granulocytes and are overexpressed in myeloid leukemia cells. PR1 induces powerful HLA-A(*)0201-restricted CD8+ T-cell responses that selectively kill myeloid leukemia cells in vitro. The detection of low frequencies of PR1-specific CD8+ T cells in patients with chronic myeloid leukemia and at higher frequencies in patients entering molecular remission after allogeneic stem cell transplantation supports the concept that there is natural immunity to PR1, which can be boosted further by vaccination to enhance immunity to leukemia. Preliminary reports indicate that PR1 peptide vaccination induces significant increases in PR1-specific CD8+ T cells, with rapid and durable remissions in some patients with myeloid leukemia. These promising early results point the way to optimizing the administration of peptide vaccines to improve the treatment of otherwise refractory myeloid leukemias.
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PMID:PR1 vaccination in myeloid malignancies. 1876 37

The serine proteases, neutrophil elastase (HNE) and proteinase 3 (PR3), are aberrantly expressed in human myeloid leukemias. T-cell responses to these proteins have been correlated with remission in patients with chronic myeloid leukemia (CML). Human PR3/HNE-specific CD8(+) T cells predominantly recognize a nonameric HLA-A2-restricted T-cell epitope called PR1 which is conserved in both Ags. However, CML patients have CD8(+) T cells in peripheral blood recognizing an additional HLA-A2 epitope termed PR2. To assess immunologic properties of these Ags, novel recombinant vaccinia viruses (rVV) expressing PR3 and HNE were evaluated in HLA-A2 transgenic (Tg) mice (HHDII). Immunization of HHDII mice with rVV-PR3 elicited a robust PR3-specific CD8(+) T-cell response dominated by recognition of PR2, with minimal recognition of the PR1 epitope. This result was unexpected, because the PR2 peptide has been reported to bind poorly to HLA. To account for these findings, we proposed that HHDII mice negatively selected PR1-specific T cells because of the presence of this epitope within murine PR3 and HNE, leading to immunodominance of PR2-specific responses. PR2-specific splenocytes are cytotoxic to targets expressing naturally processed PR3, though PR1-specific splenocytes are not. We conclude that PR2 represents a functional T-cell epitope recognized in mice and human leukemia patients. These studies are registered at www.clinicaltrials.gov as NCT00716911.
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PMID:Characterization of immunologic properties of a second HLA-A2 epitope from a granule protease in CML patients and HLA-A2 transgenic mice. 2171 1


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