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Results for “Promyelocytic Leukemia Protein”

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PubMed2026

Time-resolved mapping in calves reveals bovine herpesvirus 1 shift from mucosal replication to trigeminal ganglion neuroinvasion with promyelocytic leukemia protein-centered host-virus antagonism.

Although bovine herpesvirus 1 (BoHV-1) causes massive losses of cattle, the transition from mucosal replication to neuroinvasion remains poorly understood. Using a controlled calf model, we integrated quantitative virology and transcriptomics to map its pathogenesis and define the role of promyelocytic leukemia protein (PML). Calves inoculated intranasally and ocularly (1.4 × 106 plaque-forming units/head) were sampled daily (1-14 days post-infection, dpi) for glycoprotein B (gB) qPCR. Tissues were analyzed at 4 and 14 dpi to measure viral DNA via gB-specific qPCR, and for mRNA-seq of trigeminal ganglia (TG). Shedding peaked at 3-6 dpi, being highest in nasal samples, lower in ocular samples, and substantially lower in rectal samples, and declined by 10-14 dpi. At 4 dpi, among the tissues sampled, the tonsils exhibited the highest viral burden. TG exhibited low viral levels at 4 dpi, although they remained detectable at 14 dpi, indicating neuroinvasion. The TG program shifted from early proteostasis priming (4 dpi) to immune/extracellular matrix activation with synaptic repression (14 dpi). In MDBK/Vero cells, IFN-α resulted in higher bovine PML (bPML) levels and enlarged PML nuclear bodies (PML-NBs), reducing very early viral DNA levels, whereas BoHV-1 disrupted PML-NB integrity. The different bPML isoforms exerted different effects on viral infection. STRING analysis revealed a conserved PML-SUMO1-UBE2I-DAXX-SP100 core. These findings delineate the mucosal-to-neuronal trajectory, establish PML as both an effector and viral target in complementary in vitro systems, and identify SUMO/ubiquitin-linked proteostasis as a tractable target for antiviral intervention.IMPORTANCEAlthough bovine herpesvirus 1 (BoHV-1) remains a major challenge to cattle health, the early transition from mucosal replication to trigeminal neuroinvasion has not been clearly mapped in natural-host calves. By integrating daily shedding kinetics, tissue viral DNA profiling, and time-resolved trigeminal ganglion transcriptomics, we delineate when and how BoHV-1 reaches the sensory neurons. Promyelocytic leukemia protein (PML) is identified as a key intrinsic antiviral factor that is upregulated by IFN-α and restricts very early viral genome accumulation, while viral BoHV-1-encoded infected cell protein 0 actively dismantles PML nuclear bodies. The discovery of opposing isoform-specific PML functions and a conserved PML-SUMO proteostasis hub provides mechanistic insight into BoHV-1 immune evasion. These findings refine our understanding of the mucosal-to-neuronal trajectory of infection and highlight proteostasis-linked antiviral pathways as promising targets for intervention.

Animals↗

PubMed2024

PML::RARA and GATA2 proteins interact via DNA templates to induce aberrant self-renewal in mouse and human hematopoietic cells.

The underlying mechanism(s) by which the PML::RARA fusion protein initiates acute promyelocytic leukemia is not yet clear. We defined the genomic binding sites of PML::RARA in primary mouse and human hematopoietic progenitor cells with V5-tagged PML::RARA, using anti-V5-PML::RARA chromatin immunoprecipitation sequencing and CUT&RUN approaches. Most genomic PML::RARA binding sites were found in regions that were already chromatin-accessible (defined by ATAC-seq) in unmanipulated, wild-type promyelocytes, suggesting that these regions are "open" prior to PML::RARA expression. We found that GATA binding motifs, and the direct binding of the chromatin "pioneering factor" GATA2, were significantly enriched near PML::RARA binding sites. Proximity labeling studies revealed that PML::RARA interacts with ~250 proteins in primary mouse hematopoietic cells; GATA2 and 33 others require PML::RARA binding to DNA for the interaction to occur, suggesting that binding to their cognate DNA target motifs may stabilize their interactions. In the absence of PML::RARA, Gata2 overexpression induces many of the same epigenetic and transcriptional changes as PML::RARA. These findings suggested that PML::RARA may indirectly initiate its transcriptional program by activating Gata2 expression: Indeed, we demonstrated that inactivation of Gata2 prior to PML::RARA expression prevented its ability to induce self-renewal. These data suggested that GATA2 binding creates accessible chromatin regions enriched for both GATA and Retinoic Acid Receptor Element motifs, where GATA2 and PML::RARA can potentially bind and interact with each other. In turn, PML::RARA binding to DNA promotes a feed-forward transcriptional program by positively regulating Gata2 expression. Gata2 may therefore be required for PML::RARA to establish its transcriptional program.

Animals↗

PubMed2014

Jarid2 is induced by TCR signalling and controls iNKT cell maturation.

Jarid2 is a reported component of three lysine methyltransferase complexes, polycomb repressive complex 2 (PRC2) that methylates histone 3 lysine 27 (H3K27), and GLP-G9a and SETDB1 complexes that methylate H3K9. Here we show that Jarid2 is upregulated upon TCR stimulation and during positive selection in the thymus. Mice lacking Jarid2 in T cells display an increase in the frequency of IL-4-producing promyelocytic leukemia zinc finger (PLZF)(hi) immature invariant natural killer T (iNKT) cells and innate-like CD8(+) cells; Itk-deficient mice, which have a similar increase of innate-like CD8(+) cells, show blunted upregulation of Jarid2 during positive selection. Jarid2 binds to the Zbtb16 locus, which encodes PLZF, and thymocytes lacking Jarid2 show increased PLZF and decreased H3K9me3 levels. Jarid2-deficient iNKT cells perturb Th17 differentiation, leading to reduced Th17-driven autoimmune pathology. Our results establish Jarid2 as a novel player in iNKT cell maturation that regulates PLZF expression by modulating H3K9 methylation.

Animals↗

PubMed1977

Expression of Ia-like antigen molecules on human granulocytes during early phases of differentiation.

Human B lymphocyte antigens analogous to the murine Ia determinants were found on myeloblasts and promyelocytes but not on more mature granulocytes. This was apparent by fluorescent staining with both human alloantisera and rabbit antisera to the isolated Ia-like proteins. The cells of patients with chronic myelocytic leukemia showed this difference especially clearly. Separation of the myeloblasts and promyelocytes by multistep density gradient fractionation produced a marked enrichment of the positive cells. The remaining cells from higher density fractions were more-mature neutrophils that were essentially negative. In acute myeloid leukemia, in which myeloid cells early in differentiation predominate, the vast majority of cells were strongly positive. Similar results were obtained with normal bone marrow cells. Here also, only the early forms of the myeloid series separated by gradient centrifugation had Ia antigens. Evidence was also obtained for the presence of Ia determinants on cells with the appearance of early erythroid precursors. Support for the presence of the Ia determinants on granulocyte-macrophage committed stem cells was provided by the inhibition of granulocyte colony formation in agar cultures following preincubation of normal bone marrow with antiserum and complement. Cross absorptions with purified preparations of immature cells provided evidence for the close similarity of the antigenic determinants on both myeloblasts and B cells. A 28,000-37,000-dalton bimolecular complex obtained from myeloblast membranes contained the Ia determinants and was similar to that obtained from peripheral blood B cell membranes.

B-Lymphocytes↗

PubMed1979

Three types of Auer bodies in acute leukemia. Visualization of their protein by negative contrast after peroxidase cytochemistry.

Ten cases of acute granulocytic leukemia with blast cells containing Auer bodies (ABs) have been studied by electron microscopy after cytochemical demonstration of myeloperoxidase. The cytochemical dense reaction product has been used as a dark field to visualize unreactive protein of ABs which may then be easily identified by its negative contrast. This method has allowed us to identify three types of ABs which differ in their substructure. In type I, (five patients with promyelocytic leukemia), our study confirmed that all of the ABs consisted of a hexagonal arrangement of hollow tubes. Cells from four cases of acute myeloblastic leukemia displayed type II ABs, in which a unique pattern of protein associated in a regular linear arrangement with well defined periodicity was identified. Type III appeared characteristic of a subclass of acute myeloblastic leukemia in which large inclusions with Chediak-Higashi-like granules containing numerous micro-ABs were seen. The configuration, size, and organization of the protein in the crystal were distinct from those seen in the two other types of ABs. These features suggest that the nature of the protein in ABs may be heterogeneous.

Cytoplasmic Granules↗

PubMed1979

[Lysosomal-cation test and the prospects of its use in pathomorphological and laboratory diagnostic practice].

A cytochemical lysosome-cation test is proposed as suitable for use in diagnostic laboratories. The test is based on the detection of cationic protein and determinations of the fate of phagocytized and extracellular bacteria in inflammation foci. A method for simultaneous cytochemical detection of myeloperoxidase and cationic proteins in neutrophilic and eosinophilic granulocytes was developed. Using this method, a previously unknown variety of lysosomal granules devoid of peroxidase was detected in neutrophilic promyelocytes. The lysosomal cation test was shown to be useful for improved morphological diagnosis of leukemias, for the determination of the fate of phagocytized and non-phagocytized bacteria in inflammation foci, and of the level of nonspecific and infection resistance of the host.

Bacterial Infections↗

PubMed1978

Acute promyelocytic leukemia. A review of literature.

Acute promyelocytic leukemia is a form of acute myeloblastic leukemia characterized by hemorrhagic episodes, severe thrombocytopenia and infiltration of the marrow with "hypergranular" promyelocytes, often with multiple Auer bodies. Ultrastructurally. the promyelocytes show many splinter granules and Auer bodies with characteristic hexagonal arrangement of tubules with a periodicity of 250 A. Serum vitamin B12 and B12-binding proteins, in particular, transcobalamin I, are abnormally high. Karyotypic abnormalities include pseudodiploidy and partial deletion of the long arm of chromosome 17. Coagulation profile during bleeding episodes is usually consistent with disseminated intravascular coagulation. Greatly improved prognosis in recent years as a result of aggressive chemotherapy and anticoagulation emphasizes the need of early recognition of this clinical entity.

Adult↗

PubMed1979

Human promyelocytic leukemia cells in culture differentiate into macrophage-like cells when treated with a phorbol diester.

When suspension cultures of human promyelocytic leukemia cells (line HL60) were treated with 12-O-tetradecanoylphorbol 13-acetate (TPA; 1.6-160 nM), more than 80% of the cells adhered to the plastic substrate within 24 hr. Within the same time period the immature azurophilic granulations typical of HL60 promyelocytic cells disappeared and the nuclear chromatin became more condensed, but the nucleolus was retained. The attached cells stopped dividing and synthesizing DNA. The phenomenon was irreversible and independent of the continuous presence of TPA. Approximately 60% of the untreated cells and of TPA-treated cells bore surface Fc receptors for IgG. Under the experimental conditions used, about 10% of the TPA-treated cells were also able to phagocytize IgG-coated erythrocytes and more than 80% were able to phagocytize latex beads, but untreated controls were unable to do so. Cellular levels of NADase, acid phosphatase, and non-specific esterase were markedly increased after treatment with TPA, whereas little or no increase was seen after treatment with dimethyl sulfoxide (Me2SO), a drug that induces myeloid differentiation of HL60 cells. Peroxidase activity was lower in TPA-treated and Me2SO-treated cells than in HL60 cells. More lysozyme was found in the medium of TPA-treated cells than in the medium of untreated or Me2SO-treated cells. These data indicate that, after treatment with TPA, human promyelocytic leukemia cells can differentiate into cells that have several characteristics of macrophages.

Cell Adhesion↗

PubMed1979

Normal functional characteristics of cultured human promyelocytic leukemia cells (HL-60) after induction of differentiation by dimethylsulfoxide.

The HL-60 human promyelocytic leukemia cell line can be induced to terminally differentiate to mature myeloid cells sharing a number of functional characteristics with normal granulocytes including response to chemoattractants, development of complement receptors, phagocytosis, superoxide production, and nitroblue tetrazolium dye reduction. Hence the Me2SO-induced HL-60 cells provide a unique in vitro model for studying various important aspects of human myeloid cell differentiation.

Binding Sites↗

PubMed1975

The procoagulant factor of leukaemic promyelocytes: demonstration of immunologic cross reactivity with human brain tissue factor.

A procoagulant activity was found in the immature cells from patients with acute promyelocytic leukaemia. It was demonstrated that this activity was related to tissue factor. The protein component of tissue factor from brain extract was purified by Nemerson's technique and injected into rabbits to obtain anti-TF antibodies. Similar antibodies were produced against the promyelocyte extract. The anti-brain tissue factor antibodies neutralized the tissue factor activity of promyelocyte extract, and antibodies against immature cells were able to neutralize the tissue factor activity of human brain extract. In immunoprecipitation studies a reaction of partial identity appeared between one component of promyelocyte extract and one component of brain tissue factor. The data demonstrated that the promyelocyte procoagulant is antigenically related to brain tissue factor.

Antibodies↗

PubMed1979

Acute promyelocytic leukemia.

Acute promyelocytic leukemia (APL) is characterized by proliferation of morphologically abnormal promyelocytes and a severe bleeding diathesis. The abnormal promyelocyte is characterized by abundant, large granules, many of which are spindle-shaped. Electron microscopic appearance of the granules closely resembles that of Auer rods. The granules appear to possess tissue thromboplastin activity by both immunologic and clotting assays. Coagulation studies in APL are generally consistent with disseminated intravascular coagulation. Prolongation of the prothrombin time and elevation of fibrinogen degradation products are the tests that are most commonly abnormal. Although occasional reports indicate a favorable response of the coagulopathy to drugs that inhibit fibrinolysis, the use of prophylactic heparin appears to be the treatment of choice. The response rate of APL to chemotherapy regimens that contain an anthracycline is comparable to that of acute myelogenous leukemia. The recent description of the 15;17 chromosomal translocation which may be pathognomonic for APL is only the second example of a chromosomal marker of human neoplasia. Marked elevation of serum vitamin B12 and B12 binding proteins appears to be another characteristic feature of APL. An in vitro cell line of APL cells has been demonstrated to have the capacity to differentiate to functional polymorphonuclear leukocytes, but the cause for the maturation arrest is unknown.

Blood Coagulation Disorders↗

PubMed1979

[Initiation in vivo of blood coagulation. The role of white blood cells and tissue factor (author's transl)].

Tissue factor is an ubiquitous phospholipid-protein complex, which triggers blood coagulation through the so-called extrinsic pathway. Reactions initiated by tissue factor bypass many of the early stages of coagulation (contact phase) and involve factors VII, X, V, II and fibrinogen but also factor IX (and VIII) as it was recently demonstrated. So, it appears that tissue factor has a key-role in the haemostasic process as it has been suggested by the mildness or the absence of haemorrhagic syndrome in contact factors deficiencies. Tissue factor activity has been found in many types of cells, especially in white bloods cells. Experimental studies have demonstrated the presence of tissue factor activity in polymorphonuclears, lymphocytes, monocytes (or macrophages). This activity is enhanced by gram-negative endotoxin stimulation, inflammation, cell mediated immunologic phenomena or malignancy. These data are in good agreement with a wild range of features observed in human pathology: fibrin deposits in inflammatory lesions, disseminated intravascular coagulation (DIC) during the course of gram-negative septicemias or acute promyelocytic leukemias, local thrombi at the early phase of graft rejection. The protective effect of a phospholipase C against DIC induced in rats by tissue factor infusion suggests in the future, a specific therapy would be possible in man that, in the frequent clinical conditions involving clotting activation through tissue factor pathway.

Animals↗

PubMed1979

Chromatin conformation during cell differentiation of human myeloid leukemia cells.

A novel human promyelocytic leukemia cell line (HL-60) has been shown to form terminally differentiated granulocytes in the presence of dimethyl-sulfoxide (DMSO), some other chemicals, or colony stimulating factor. Compared to chromatin from HL-60 cells, chromatin from DMSO treated HL-60 cells showed an enrichment in low temperature melting material. The decrease in thermostability of chromatin from HL-60 cells after DMSO treatment is similar to the shift in thermostability of chromatin from human lymphocytes after stimulation with phytohemagglutinin (PHA). These results suggest that changes in the thermostability of chromatin may not be specific for cell differentiation or PHA stimulation.

Adult↗

PubMed1979

Specific changes in the surface glycoprotein pattern of human promyelocytic leukemic cell line HL-60 during morphologic and functional differentiation.

The human promyelocytic leukemia cell line HL-60 can be induced to undergo morphological and functional differentiation in vitro by various low molecular weight compounds. The cellular morphology changes from blastoid appearance to that of granulocytes and the cells acquire the ability to phagocytize. We here report that the surface glycoproteins specifically change during this differentiation, as shown by the neuraminidase/galactose oxidase/NaB3H4 surface-labeling technique followed by polyacrylamide slab gel electrophoresis. The most prominent change is the loss of the major glycoprotein band typical for the blast cells which has an apparent molecular weight of 160,000 and the appearance of a major surface glycoprotein band with an apparent molecular weight of 130,000. Expression of the 130,000 molecular weight band correlates with the appearance of phagocytic and chemotactic activities of the cells. It has the same molecular weight as the major surface glycoprotein of freshly isolated human blood granulocytes.

Cell Differentiation↗

PubMed1978

The sequential appearance of Ia-like antigens and two different complement receptors during the maturation of human neutrophils.

Ia antigens and two different types of complement (C) receptors appeared on membrane surfaces in a distinct sequence during the maturation of human neutrophils. Taking advantage of the finding that neutrophil celll density increased with maturation, density gradient centrifugation was used to separate neutrophils into fractions that were greatly enriched in cells representing individual stages of differentiation. Myeloblasts, the earliest cells recognized in the myeloid series of both normal and myelogenous leukemic individuals, expressed Ia determinants, whereas Ia determinants were absent or diminished on the majority of promyelocytes and completely undetectable on more mature granulocytes. Double marker studies demonstrated that Ia determinants were lost from the membrane of developing myeloid cells before the appearance of any type of C receptor. In the next phase of maturation defined by surface markers, neutrophils acquired a CR2-type C receptor (C3d receptor) that was similar in specificity to CR2 of B lymphocytes. This stage of maturation approximately corresponded to the myelocyte-metamyelocyte stage defined by standard morphologic criteria, and preceded the third stage of surface marker maturation when developing neutrophils began to express CR1-type C receptors (immune adherence, C4b-C3b receptors) in addition to CR2. In the final stage of surface marker-defined maturation, CR2 was lost from high density polymorphonuclear neutrophils and CR1 was maximally expressed. Normal blood polymorphonuclear neutrophils contained only 17% of CR2-bearing cells and these were shown to be of lower density than the majority of neutrophils that expressed only CR1. There was some variation in the correlation of surface marker expression and maturation stage defined by morphologic criteria, but in all cases the sequence of marker appearance was the same: Ia leads to CR2 leads to CR1CR2 leads to CR1.

Binding Sites↗