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Results for “Granulocyte Precursor Cells”

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PubMed1987

Inhibition of growth but not differentiation of normal and leukemic myeloid cells by methylthioadenosine.

Methylthioadenosine (MTA), a coproduct of polyamine biosynthesis, is known to inhibit proliferation in a variety of cell culture systems. In this paper, we show that while MTA inhibits the growth of the human promyelocytic cell line HL-60, it does not interfere with retinoic acid-induced granulocytic or phorbol ester-induced monocytic differentiation of these cells. MTA also inhibits proliferation induced by colony stimulating activity of normal human granulocytic precursor cells grown in suspension culture but does not suppress terminal differentiation of these cells. In contrast to the lack of effect of MTA on granulocytic differentiation which we report here, others have shown that MTA prevents terminal differentiation of murine erythroleukemia cells. That MTA is a normal cellular constituent which inhibits proliferation but not differentiation of normal granulopoietic cells and may have opposing effects on immature cells of erythroid lineage suggests a possible role for this compound in the regulation of hematopoiesis. In addition, MTA may be useful for studying the process of differentiation in the absence of cell proliferation in granulopoietic cells.

Adenosine↗

PubMed1985

Stimulation of human neutrophilic granulocyte chemotaxis by monoclonal antibodies.

Two mouse monoclonal antibodies, L12.2 and S5.22, were developed that are specific for human neutrophilic granulocytes and produce a twofold to threefold stimulation of n-formyl-methionine-leucyl-phenylalanine (FMLP)-induced chemotaxis. Stimulation of chemotaxis by the antibodies is specific for FMLP and is concentration dependent. L12.2 appears to be more potent in stimulating chemotaxis and is isotypically distinct from S5.22. In addition, although L12.2 reacts only with mature peripheral blood granulocytes, S5.22 reacts with leukemic cells of both myeloid and monocytic origin and with immature granulocyte precursor cells. This suggests that L12.2 interacts with an antigen that appears late in the differentiation pathway, whereas S5.22 binds to an antigen that is present throughout the myeloid lineage. By means of the under-agarose and Boyden chamber techniques, L12.2, but not S5.22, by itself was also found to be a potent granulocyte chemoattractant. Cells in a gradient of L12.2 display polarized and oriented morphology. L12.2 alone, but not S5.22, also stimulates granulocyte phagocytosis and induces superoxide anion production. Neither L12.2 nor S5.22 affected the release of myeloperoxidase or lysozyme from granulocytes either alone or in combination with FMLP, C5a, or the tumor promoter, 12-O-tetradecanoyl-phorbol-13-acetate (TPA). These results suggest that L12.2 interacts with a single antigenic determinant on granulocytes that is involved in chemotaxis, phagocytosis, and superoxide anion release.

Animals↗

PubMed1976

The reversal of methotrexate cytotoxicity to mouse bone marrow cells by leucovorin and nucleosides.

The cytotoxic effect of methotrexate (MTX) for mouse bone marrow cells has been studied by in vitro of the granulocyte precursor cell (CFU-C) in a medium containing dialyzed fetal calf serum and dialyzed L-cell supernatant. The formation of 50-cell colonies was inhibited to 50% of control by 10(-8) M MTX. Further increases in MTX concentration rapidly abolished colony formation by CFU-C. The potential of leucovorin and nucleosides to rescue the CFU-C from MTX toxicity was studied. Toxicity of 10(-7) M MTX was completely reversed by equimolar concentrations of leucovorin, but with higher MTX concentrations, relatively more leucovorin was required. While 10(-5) M MTX was rescued by 10(-3) M leucovorin, rescue of the toxic effect of 10(-4) M MTX by 10(-3) M leucovorin was not observed. In contrast to the rescue by Leucovorin, toxicity of all MTX concentrations up to 10(-4) M was completely prevented by 10(-5) M thymidine with 10(-5) M adenosine, inosine, or hypoxanthine. Single nucleosides or thymidine with guanosine were ineffective, as were lower concentrations (less than or equal to 10(-6)M) of the effective combinations. Thus, while leucovorin reversed the MTX toxicity to CFU-C competitively, rescue by nucleosides was noncompetitive. The significance and possible usefulness of these findings for chemotherapeutic protocols are discussed.

Adenosine↗

PubMed1998

Granulocyte colony-stimulating factor activates protein kinase A in granulocytic but not monocytic precursors or neutrophils.

Granulocyte colony-stimulating factor (G-CSF) regulates survival, proliferation, differentiation, and activation of myeloid cells. G-CSF-R signaling mechanisms other than tyrosine kinase activation have not been documented. We explored the potential involvement of cAMP-dependent protein kinase A (PKA) in G-CSF-R signal transduction. In this report, we provide the first direct evidence of PKA modulation by G-CSF-R. G-CSF treatment of granulocytic precursor cell lines (HL-60, NFS-60, KG-1) resulted in PKA activation, measured by phosphorylation of Kemptide, a peptide substrate. In contrast, the myelomonocytic cell lines (WEHI-3B,U-937) and peripheral blood neutrophils (PMNC) showed a rapid decrease in PKA activity in response to G-CSF. H-89, a specific inhibitor of PKA, blocked G-CSF-induced PKA activation in HL-60 cells but did not affect ligand-induced downmodulation of G-CSF-R. Indomethacin, an inhibitor of the cyclooxygenase pathway and prostaglandin synthesis, did not inhibit PKA induction in G-CSF-treated HL-60 cells. Our results demonstrate the involvement of PKA in G-CSF-R signal transduction and suggest a lineage-restricted, developmental stage-specific regulation of this pathway in myeloid cells.

Animals↗

PubMed1988

Murine granulocyte colony-stimulating factor: actions on normal and leukemic cells.

Granulocyte colony-stimulating factor (G-CSF) is a strongly conserved glycoprotein which induces the survival, proliferation and differentiation of neutrophilic granulocyte precursor cells and functionally activates mature blood neutrophils. Among the family of colony-stimulating factors, G-CSF is the most potent inducer of terminal differentiation to granulocytes and macrophages of leukemic myeloid cell lines. The actions of G-CSF are mediated through a small number of specific cellular receptors which are induced to internalize and accumulate within the cell after binding of G-CSF at 37 degrees C. G-CSF receptors can be lost from the cell surface not only by binding G-CSF, but indirectly by other factors including GM-CSF, Multi-CSF, bacterial lipopolysaccharides, chemotactic peptides and phorbol esters, depending on cell type. Possible relationships of these processes to the mechanism of action of G-CSF are discussed.

Animals↗

PubMed1981

My-1, new myeloid-specific antigen identified by a mouse monoclonal antibody.

Antibody-secreting hybridomas were produced by fusion of P3-NS1/1Ag--4-1 mouse plasmacytoma cells with splenocytes from a mouse immunized with HL-60 human promyelocytic leukemia cells. A cloned hybridoma cell line was identified that secreted antibody against a cell surface antigen expressed on all normal human peripheral blood granulocytes, on bone marrow granulocytic precursor cells, and on blast cells from 3 of 15 patients with nonlymphoid leukemia. However, the antibody did not react with normal peripheral blood lymphocytes, monocytes, platelets, or red cells, or with blast cells from 20 patients with acute lymphoblastic leukemia or from 5 patients with lymphoma. This monoclonal antibody identified a granulopoietic differentiation antigen (designated My-1) and may prove useful in the subclassification on nonlymphoid leukemia and in the investigation of hematopoiesis.

Animals↗

PubMed2003

Immunophenotypic profile of adult acute myeloid leukemia (AML): analysis of 267 cases in Thailand.

Little data exists in Thailand and other Southeast Asian countries regarding the biological characteristics of adult acute myeloid leukemia (AML). In this study, we performed a flow cytometric analysis of 267 Thai adult AML cases to delineate the pattern of leukemic cell surface antigens. Forty-eight cases (18%) were identified as acute promyelocytic leukemia (M3) and 219 cases as non-M3. The most frequent subtype of AML in Thailand was M1/M2 and the least frequent was M7. M3 immunophenotypes were characterized by their unique lack of expression of CD34 and HLA-DR as contrast to the high mean expression of 50% and 70%, respectively, in non-M3. Overall, 60% of cases expressed CD34. Aberrant lymphoid antigens were uniquely seen in specific subtypes of Thai AML, including CD19 (33% of non-M3 vs 23% of M3) and CD2 (12% of M3 vs 2% of non-M3). CD56 was frequently expressed in both M3 and non-M3 while CD16 appeared to be associated with M4/M5 (24% of cases) and CD7 with M1/M2 (21% of cases). Eighty-one percent of non-M3 expressed CD38 while only 53% of M3 did. We found that most Thai adult AML patients were on average 15-20 years younger than those of the West or Japan with only 25% of Thai cases over 60 years of age, although the immunophenotypes were not markedly different. Biological studies of acute leukemia in various countries should help to provide epidemiological clues that play a role in the pathogenesis of leukemia in different geographic regions of the world. Our study represents the largest series of AML ever investigated in the Southeast Asian region.

Acute Disease↗

PubMed1993

Expression of the transforming growth factor alpha protooncogene in differentiating human promyelocytic leukemia (HL-60) cells.

The process of myeloid differentiation in human promyelocytic leukemia cells (HL-60) is accompanied by the coordinate expression of numerous protooncogenes. To investigate the expression of transforming growth factor alpha (TGF-alpha) in myeloid differentiation, HL-60 cells were induced to differentiate into granulocytes with 1.25% dimethyl sulfoxide, 0.2 microM all-trans retinoic acid, or 500 microM N6,O2-dibutyryladenosine-3'5'-cyclic monophosphate or differentiated along the monocyte/macrophage pathway with 0.1 microM phorbol-12-myristate-13-acetate. Using Northern blot analyses, TGF-alpha transcripts were detected within 24 h of treatment in cells differentiating toward granulocytes; maximal levels of gene expression were reached after 3 days or later and remained essentially constant throughout the observation period. These cells released TGF-alpha protein, as demonstrated by analysis of the incubation medium. In contrast, no TGF-alpha RNA or protein was detectable in HL-60 cell cultures when induced with phorbol-12-myristate-13-acetate. Epidermal growth factor receptor transcripts could not be detected either in undifferentiated or in differentiated HL-60 cells; therefore it appears as if an autocrine loop involving TGF-alpha in HL-60 cells is unlikely. In conclusion, the results demonstrate, for the first time, the expression of TGF-alpha in human granulocyte precursor cells. Our findings may indicate novel regulatory pathways in hematopoiesis.

Cell Differentiation↗

PubMed1996

Granulocyte colony-stimulating factor expression from transduced vascular smooth muscle cells provides sustained neutrophil increases in rats.

Granulocyte colony-stimulating factor (G-CSF) regulates granulocyte precursor cell proliferation, neutrophil survival, and activation. Cyclic hematopoiesis, a disease that occurs both in humans and grey collie dogs is characterized by cyclical variations in blood neutrophils. Although the underlying molecular defect is not known, long-term daily administration of recombinant G-CSF eliminates the severe recurrent neutropenia, indicating that expression of G-CSF by gene therapy would be beneficial. As a prelude to preclinical studies in affected collie dogs, we monitored hematopoiesis in rats receiving vascular smooth muscle cells transduced to express G-CSF. Cells transduced with LrGSN, a retrovirus expressing rat G-CSF, were implanted in the carotid artery and control animals received cells transduced with LASN, a retrovirus expressing human adenosine deaminase (ADA). Test animals showed significant increases in neutrophil counts for at least 7 weeks, with mean values of 3,670 +/- 740 cells/microliter in comparison to 1,870 +/- 460 cells/microliter in controls (p < 0.001). Thus, in rats G-CSF gene transfer targeted at vascular smooth muscle cells initiated sustained production of 1,800 neutrophils/microliter, a cell number that would provide clinical benefit to patients. Lymphocytes, red cells and platelets were not different between control and test animals (p > 0.05). These studies indicate that retrovirally transduced vascular smooth muscle cells can provide sustained clinically useful levels of neutrophils in vivo.

Adenosine Deaminase↗

PubMed1988

Tumor necrosis factor and human hematopoiesis: I. Kinetics and diversity of human bone marrow cell response to recombinant tumor necrosis factor alpha in short-term suspension cultures in vitro.

The response of normal human bone marrow-derived granulocyte macrophage progenitor cells (GM-CFC) to human recombinant tumor necrosis factor alpha (TNF-alpha) was studied in short-term suspension cultures, in the presence or absence of human placenta-derived colony-stimulating factors (CSF). The effect of rTNF-alpha on GM-CFC was correlated with its influence on more mature progeny, as defined by standard morphological criteria, and was related to both dose of rTNF-alpha and length of exposure. After very short-term exposure (2 h), "inactivation" of a substantial number of GM-CFC was observed only in the presence of very high rTNF-alpha doses (1 x 10(4) ng/ml). When the exposure was prolonged to 16 h, a significant killing of both day 8 (GM-CFC8d) and day 14 (GM-CFC14d) progenitor cells was detected in the presence of 10 ng of rTNF-alpha/ml. Exposure for 5 days resulted in a further increase in the GM-CFC killing. Presence of yet unknown factor(s) in human placenta-conditioned medium sensitized GM-CFC to the action of rTNF-alpha. By morphological analysis of marrow cells, it was found that rTNF-alpha inhibited growth and/or recruitment of granulocytic precursor cells and caused inhibition of their differentiation. This effect was not dose dependent above 1 x 10(1) ng/ml. The presence of rTNF-alpha slightly promoted dose-dependent differentiation along the macrophage pathway. rTNF-alpha appeared to promote eosinophilic differentiation, also in a dose-dependent manner.

Colony-Stimulating Factors↗

PubMed1989

Evidence for a factor in normal human serum that induces human neutrophilic granulocyte end-stage maturation in vitro.

The end-stage maturation of neutrophilic granulocyte precursor cells isolated from normal human bone marrow by Ficoll density centrifugation was studied in a liquid culture assay system used previously to study the maturation of guinea pig granulocyte precursors. Dialyzed normal human serum induced end-stage morphological maturation of human granulocyte precursors and this induction was proportional to a serum level of up to 5.0% in the assay medium. At serum concentrations greater than 5.0% a pronounced inhibition of maturation was observed. Passage of serum through a DEAE-Fractogel 650S column equilibrated with 0.01 M phosphate buffer (pH 7.0) resulted in the binding of the end-stage granulocyte maturation factor to the column. The activity eluted from the column in a fraction containing 17% of the starting serum protein that was inhibitor-free and was also capable of inducing the appearance of granulocyte alkaline phosphatase, a specific biochemical marker for granulocyte end-stage maturation. GMF is most likely a protein since it was destroyed by protease digestion. The data also indicate that neither purified human transferrin nor human recombinant granulocyte colony-stimulating factor can substitute for human serum GMF as a granulocyte end-stage maturation factor in this assay system. It was observed, however, that purified human transferrin greatly potentiated the effect of GMF suggesting that transferrin plays a supporting role in the end-stage maturation of human granulocytes in vitro. To our knowledge the evidence presented here indicates for the first time the existence of a neutrophilic granulocyte end-stage maturation factor in normal human serum.

Alkaline Phosphatase↗

PubMed1980

Clonal analysis of proliferation and differentiation of paired daughter cells: action of granulocyte-macrophage colony-stimulating factor on granulocyte-macrophage precursors.

Mouse granulocyte-macrophage progenitor cells were stimulated to divide by the granulocyte-macrophage colony-stimulating factor (GM-CSF). The two daughter cells were separated; one daughter was transferred to medium containing a high concentration of GM-CSF, the other to medium containing a low concentration. Daughter cell-derived clones in the presence of 2500 units of GM-CSF had average cell cycle times 3.5 +/- 2.5 (SEM) hr shorter than clones derived from the paired daughter cell stimulated by 50 units of GM-CSF. Final colony size achieved after stimulation by 50 units of GM-CSF was always smaller than that of colonies stimulated by 2500 units of GM-CSF. In 8 of 41 instances, colonies stimulated by 50 units of GM-CSF developed, or were composed only of, macrophage populations in contrast to the granulocytic composition of colonies derived from the paired daughter cell growing in the presence of 2500 units of GM-CSF. The regulator GM-CSF appears able to directly influence cell cycle times and the pathway of differentiation entered by many bipotential granulocyte-macrophage precursor cells.

Animals↗

PubMed1997

Protein tyrosine kinases in granulocyte colony stimulating factor receptor signal transduction, myeloid cell proliferation, and neutrophil activation.

Granulocyte colony-stimulating factor (G-CSF) plays an important role in the growth and maturation of granulocytic precursor cells. Although the interaction between G-CSF and its receptor (G-CSF-R) is an obligatory event during proliferation and differentiation of myeloid cells, the signal transduction mechanisms leading to these effects are not completely known. We investigated the kinetics of protein tyrosine kinase (PTK) activation in G-CSF-R signal transduction in myeloid leukemic cell lines and peripheral blood neutrophils. G-CSF treatment of myeloid cell-lines (HL-60, KG-1, NFS-60) and neutrophils resulted in a rapid increase in PTK activity. This induction was inhibited by an anti-G-CSF monoclonal antibody and various PTK-specific inhibitors. PTK activity was important for proliferation of myeloid cells; its inhibition resulted in decreased proliferation and clonogenicity of these cells. PTK-induction was not involved in G-CSF-R expression, internalization or recycling, but was partially responsible for up-regulation of CD11b expression on neutrophils. In contrast to neutrophilic cell-lines, the myelo-monocytic cell lines (U-937, WEHI-3B) showed no change in PTK levels in response to G-CSF. The results indicate that the G-CSF-R-mediated PTK up-regulation may be a neutrophil-lineage-restricted signal, and that PTK may play an important role in the proliferation of neutrophil-precursors and functional activation of mature neutrophils.

Animals↗

PubMed2004

The transcriptional program of terminal granulocytic differentiation.

To characterize the transcriptional program that governs terminal granulocytic differentiation in vivo, we performed comprehensive microarray analyses of human bone marrow populations highly enriched in promyelocytes (PMs), myelocytes/metamyelocytes (MYs), and neutrophils (bm-PMNs). These analyses identified 11 310 genes involved in differentiation, of which 6700 were differentially regulated, including previously unidentified effector proteins and surface receptors of neutrophils. Differentiation of PMs toward MYs was accompanied by a marked decline of proliferative and general cellular activity as defined by down-regulation of E2 promoter binding factor (E2F) target genes; cyclin dependent kinases 2, 4, and 6; and various metabolic, proteasomal, and mitochondrial genes. Expression patterns of apoptosis genes indicated death control by the p53 pathway in PMs and by death receptor pathways in bm-PMNs. Effector proteins critical for host defense were expressed successively throughout granulocytic differentiation, whereas receptors and receptor ligands essential for the activation of the host defense program were terminally up-regulated in bm-PMNs. The up-regulation of ligand-receptor pairs, which are defined inducers as well as target genes of nuclear factor-kappa B (NF-kappa B), suggests a constitutive activation of NF-kappa B in bm-PMNs by autocrine loops. Overall, these results define a granulocytic differentiation model governed by a highly coordinated fail-safe program, which promotes completion of differentiation before cells gain responsiveness toward activating stimuli that accompany infections.

Apoptosis↗

PubMed1981

Colony formation by bone marrow cells after incubation with neuraminidase. II. Sensitivity of erythroid progenitor cells for burst promoting activity and erythropoietin and restoration of reduced spleen colony formation in mice pretreated with desialated erythrocyte membrane fragments.

Incubation of bone marrow cells (BMC) with neuraminidase (NA) reduces their ability to form colonies in the spleen of lethally irradiated mice. In vivo the largest reduction was observed in the erythrocytic colonies, whereas in vitro an inhibiting effect of NA incubation was observed on the plating efficiency of erythrocyte precursors (CFUE and day 7 BFUE). Masking of the receptors for neuraminidase-treated cell surface determinants in the recipient's body by infection of desialated erythrocytes (NA-Ery) or erythrocyte membrane fragments (NA-Efr) did largely restore the reduced colony formation of NA-BMC with respect to both the total number of spleen colonies and their type. Pretreatment of irradiated host with NA-Ery, but with NA-Efr, led to a slight polycythemia as judged by the number of erythrocytic and undifferentiated colonies as well as by the surface colony diameter. The reduced erythrocytic colony formation of NA-BMC was considerably enhanced in anemic irradiated recipients (from 25-70% of respective controls). Under all experimental circumstances the erythrocytic colony formation of NA-BMC never exceeded that of normal BMC (N-BMC). Further, in normal or anemic recipients whether or not treated with NA-Efr, the diameters of the spleen surface colonies in NA-BMC injected animals were smaller than in recipients of control-incubated BMC. In vitro experimentation indicated that the reduced plating efficiency of CFUE and BFUE following incubation could not be attributed to a decreased sensitivity to erythropoietin. However, day 7 BFUE with deficient cell surface sialic acid residues had a decreased sensitivity to burst promoting activity. Among several other explanations, our data support the possibility that the desialated colony forming cells that give rise to erythrocytic colonies in vivo have higher requirements for early regulatory factors than granulocytic precursor cells. In contrast to the normal postirradiation situation the level of these factors could be increased in recipients, which are bled subsequently to irradiation. Evidence is presented in support of our concept that neuraminidase-treated CFU are fully capable to exhibit normal, although delayed, colony formation in vivo in animals with covered receptors for galactosyl residues.

Animals↗

PubMed1976

Cloning of canine hematopoietic cells in vitro.

A modified cloning method of the agar culture of canine bone marrow cells was described. A high efficiency of colony formation was seen only after addition to the agar medium of the colony-stimulating activity (CSA) from different sources. Dog serum in a 20% concentration was used in this case. With the optimal CSA concentration there was seen a linear relationship between the number of explanted cells and the number of produced colonies. This method is suitable for determination of committed granulocyte precursor cells, as well as for the study of potential humoral regulators of granulocytopoiesis in dogs.

Animals↗

PubMed1978

Bone marrow colony-forming cells in acute drug-induced agranulocytosis.

The capacity to differentiate and form colonies in vitro by bone marrow granulocytic precursor cells and its evolution were studied in eight cases of drug-induced acute agranulocytosis. In three cases colonies and clusters count were normal or high. These cases were probably immunological agranulocytosis. In the five other cases this number was very low and returned to normal from three to thirteen days. These were probably cases of marrow suppression by the drug.

Acute Disease↗

PubMed1994

Granulocytic sarcoma presenting as a diffuse renal mass before hematological manifestations of acute myelogenous leukemia.

Granulocytic sarcoma is a rare tumor composed of granulocytic precursor cells. The most common sites of involvement include the bones, soft tissue, lymph nodes and skin. Granulocytic sarcoma usually develops as a delayed manifestation of the disease process in patients with known acute myelogenous leukemia. To our knowledge we report the first case of renal granulocytic sarcoma presenting as the first sign of acute myelogenous leukemia. Computerized tomography and magnetic resonance imaging revealed diffuse nonspecific global tumor infiltration of the kidney and ureter. Renal granulocytic sarcoma was diagnosed on open renal biopsy and acute myelogenous leukemia on bone marrow biopsy. There has been partial response to combination chemotherapy. Renal granulocytic sarcoma may diffusely involve the kidney as the only manifestation of acute myelogenous leukemia and it should be included in the differential diagnosis of the many disease entities with global renal involvement since initial treatment is combination chemotherapy.

Diagnosis, Differential↗